Skip to main content
SpringerLink
Log in

Penicillin-Binding Proteins and β-Lactam Resistance

  • Chapter
  • First Online:
Antimicrobial Drug Resistance

Abstract

Resistance to β-lactams has arisen in a variety of ways. In this chapter, we consider those cases where resistance results from the expression of targets, the penicillin-binding proteins, which have a “low affinity” for the drugs. In the last three decades, different resistance mechanisms that involve the PBPs have been uncovered in important human pathogens such as Staphylococcus aureus, Enterococci, Streptococcus pneumoniae, and Neisseria.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Tipper DJ, Strominger JL. Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine. Proc Natl Acad Sci U S A. 1965;54(4):1133–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wise Jr EM, Park JT. Penicillin: its basic site of action as an inhibitor of a peptide cross-linking reaction in cell wall mucopeptide synthesis. Proc Natl Acad Sci U S A. 1965;54(1):75–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Blumberg PM, Strominger JL. Isolation by covalent affinity chromatography of the penicillin-binding components from membranes of Bacillus subtilis. Proc Natl Acad Sci U S A. 1972;69(12):3751–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Joris B, Ledent P, Dideberg O, Fonze E, Lamotte-Brasseur J, Kelly JA, et al. Comparison of the sequences of class A beta-lactamases and of the secondary structure elements of penicillin-recognizing proteins. Antimicrob Agents Chemother. 1991;35(11):2294–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pares S, Mouz N, Petillot Y, Hakenbeck R, Dideberg O. X-ray structure of Streptococcus pneumoniae PBP2x, a primary penicillin target enzyme. Nat Struct Biol. 1996;3(3):284–9.

    Article  CAS  PubMed  Google Scholar 

  6. Lobkovsky E, Moews PC, Liu H, Zhao H, Frere JM, Knox JR. Evolution of an enzyme activity: crystallographic structure at 2-A resolution of cephalosporinase from the ampC gene of Enterobacter cloacae P99 and comparison with a class A penicillinase. Proc Natl Acad Sci U S A. 1993;90(23):11257–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Oliva M, Dideberg O, Field MJ. Understanding the acylation mechanisms of active-site serine penicillin-recognizing proteins: a molecular dynamics simulation study. Proteins. 2003;53(1):88–100.

    Article  CAS  PubMed  Google Scholar 

  8. Sauvage E, Kerff F, Terrak M, Ayala JA, Charlier P. The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev. 2008;32(2):234–58. doi:10.1111/j.1574-6976.2008.00105.x.

    Article  CAS  PubMed  Google Scholar 

  9. Bertsche U, Breukink E, Kast T, Vollmer W. In vitro murein peptidoglycan synthesis by dimers of the bifunctional transglycosylase-transpeptidase PBP1B from Escherichia coli. J Biol Chem. 2005;280(45):38096–101.

    Article  CAS  PubMed  Google Scholar 

  10. Born P, Breukink E, Vollmer W. In vitro synthesis of cross-linked murein and its attachment to sacculi by PBP1A from Escherichia coli. J Biol Chem. 2006;281(37):26985–93.

    Article  CAS  PubMed  Google Scholar 

  11. Schiffer G, Holtje JV. Cloning and characterization of PBP 1C, a third member of the multimodular class A penicillin-binding proteins of Escherichia coli. J Biol Chem. 1999;274(45):32031–9.

    Article  CAS  PubMed  Google Scholar 

  12. Schwartz B, Markwalder JA, Wang Y. Lipid II: total synthesis of the bacterial cell wall precursor and utilization as a substrate for glycosyltransfer and transpeptidation by penicillin binding protein (PBP) 1b of Escherichia coli. J Am Chem Soc. 2001;123(47):11638–43.

    Article  CAS  PubMed  Google Scholar 

  13. Terrak M, Ghosh TK, van Heijenoort J, Van Beeumen J, Lampilas M, Aszodi J, et al. The catalytic, glycosyl transferase and acyl transferase modules of the cell wall peptidoglycan-polymerizing penicillin-binding protein 1b of Escherichia coli. Mol Microbiol. 1999;34(2):350–64.

    Article  CAS  PubMed  Google Scholar 

  14. Di Guilmi AM, Dessen A, Dideberg O, Vernet T. The glycosyltransferase domain of penicillin-binding protein 2a from Streptococcus pneumoniae catalyzes the polymerization of murein glycan chains. J Bacteriol. 2003;185(15):4418–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Zapun A, Philippe J, Abrahams KA, Signor L, Roper DI, Breukink E, et al. In vitro reconstitution of peptidoglycan assembly from the Gram-positive pathogen Streptococcus pneumoniae. ACS Chem Biol. 2013;8(12):2688–96. doi:10.1021/cb400575t.

    Article  CAS  PubMed  Google Scholar 

  16. Kohlrausch U, Holtje JV. Analysis of murein and murein precursors during antibiotic-induced lysis of Escherichia coli. J Bacteriol. 1991;173(11):3425–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Banzhaf M, van den Berg van Saparoea B, Terrak M, Fraipont C, Egan A, Philippe J, et al. Cooperativity of peptidoglycan synthases active in bacterial cell elongation. Mol Microbiol. 2012;85(1):179–94. doi:10.1111/j.1365-2958.2012.08103.x.

    Article  CAS  PubMed  Google Scholar 

  18. Piette A, Fraipont C, Den Blaauwen T, Aarsman ME, Pastoret S, Nguyen-Disteche M. Structural determinants required to target penicillin-binding protein 3 to the septum of Escherichia coli. J Bacteriol. 2004;186(18):6110–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Harris F, Brandenburg K, Seydel U, Phoenix D. Investigations into the mechanisms used by the C-terminal anchors of Escherichia coli penicillin-binding proteins 4, 5, 6 and 6b for membrane interaction. Eur J Biochem. 2002;269(23):5821–9.

    Article  CAS  PubMed  Google Scholar 

  20. Amanuma H, Strominger JL. Purification and properties of penicillin-binding proteins 5 and 6 from Escherichia coli membranes. J Biol Chem. 1980;255(23):11173–80.

    CAS  PubMed  Google Scholar 

  21. Baquero MR, Bouzon M, Quintela JC, Ayala JA, Moreno F. dacD, an Escherichia coli gene encoding a novel penicillin-binding protein (PBP6b) with DD-carboxypeptidase activity. J Bacteriol. 1996;178(24):7106–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Korat B, Mottl H, Keck W. Penicillin-binding protein 4 of Escherichia coli: molecular cloning of the dacB gene, controlled overexpression, and alterations in murein composition. Mol Microbiol. 1991;5(3):675–84.

    Article  CAS  PubMed  Google Scholar 

  23. Romeis T, Holtje JV. Penicillin-binding protein 7/8 of Escherichia coli is a DD-endopeptidase. Eur J Biochem. 1994;224(2):597–604.

    Article  CAS  PubMed  Google Scholar 

  24. Botta GA, Park JT. Evidence for involvement of penicillin-binding protein 3 in murein synthesis during septation but not during cell elongation. J Bacteriol. 1981;145(1):333–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. de Pedro MA, Donachie WD, Holtje JV, Schwarz H. Constitutive septal murein synthesis in Escherichia coli with impaired activity of the morphogenetic proteins RodA and penicillin-binding protein 2. J Bacteriol. 2001;183(14):4115–26.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Den Blaauwen T, Aarsman ME, Vischer NO, Nanninga N. Penicillin-binding protein PBP2 of Escherichia coli localizes preferentially in the lateral wall and at mid-cell in comparison with the old cell pole. Mol Microbiol. 2003;47(2):539–47.

    Article  Google Scholar 

  27. Wientjes FB, Nanninga N. Rate and topography of peptidoglycan synthesis during cell division in Escherichia coli: concept of a leading edge. J Bacteriol. 1989;171(6):3412–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bertsche U, Kast T, Wolf B, Fraipont C, Aarsman ME, Kannenberg K, et al. Interaction between two murein (peptidoglycan) synthases, PBP3 and PBP1B, in Escherichia coli. Mol Microbiol. 2006;61(3):675–90. doi:10.1111/j.1365-2958.2006.05280.x.

    Article  CAS  PubMed  Google Scholar 

  29. Higgins ML, Shockman GD. Study of cycle of cell wall assembly in Streptococcus faecalis by three-dimensional reconstructions of thin sections of cells. J Bacteriol. 1976;127(3):1346–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lleo MM, Canepari P, Satta G. Bacterial cell shape regulation: testing of additional predictions unique to the two-competing-sites model for peptidoglycan assembly and isolation of conditional rod-shaped mutants from some wild-type cocci. J Bacteriol. 1990;172(7):3758–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tsui HC, Boersma MJ, Vella SA, Kocaoglu O, Kuru E, Peceny JK, et al. Pbp2x localizes separately from Pbp2b and other peptidoglycan synthesis proteins during later stages of cell division of Streptococcus pneumoniae D39. Mol Microbiol. 2014;94(1):21–40. doi:10.1111/mmi.12745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pinho MG, Errington J. Dispersed mode of Staphylococcus aureus cell wall synthesis in the absence of the division machinery. Mol Microbiol. 2003;50(3):871–81.

    Article  CAS  PubMed  Google Scholar 

  33. Massidda O, Anderluzzi D, Friedli L, Feger G. Unconventional organization of the division and cell wall gene cluster of Streptococcus pneumoniae. Microbiology. 1998;144(Pt 11):3069–78.

    Article  CAS  PubMed  Google Scholar 

  34. de Pedro MA, Holtje JV, Schwarz H. Fast lysis of Escherichia coli filament cells requires differentiation of potential division sites. Microbiology. 2002;148(Pt 1):79–86.

    Article  PubMed  Google Scholar 

  35. Giesbrecht P, Kersten T, Maidhof H, Wecke J. Staphylococcal cell wall: morphogenesis and fatal variations in the presence of penicillin. Microbiol Mol Biol Rev. 1998;62(4):1371–414.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Pucci MJ, Hinks ET, Dicker DT, Higgins ML, Daneo-Moore L. Inhibition of beta-lactam antibiotics at two different times in the cell cycle of Streptococcus faecium ATCC 9790. J Bacteriol. 1986;165(3):682–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jevons MP, Coe AW, Parker MT. Methicillin resistance in staphylococci. Lancet. 1963;1:904–7.

    Article  CAS  PubMed  Google Scholar 

  38. Deurenberg RH, Stobberingh EE. The evolution of Staphylococcus aureus. Infect Genet Evol. 2008;8(6):747–63. doi:10.1016/j.meegid.2008.07.007.

    Article  CAS  PubMed  Google Scholar 

  39. Kos VN, Desjardins CA, Griggs A, Cerqueira G, Van Tonder A, Holden MT, et al. Comparative genomics of vancomycin-resistant Staphylococcus aureus strains and their positions within the clade most commonly associated with Methicillin-resistant S. aureus hospital-acquired infection in the United States. MBio. 2012;3(3):e00112–12. doi:10.1128/mBio.00112-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Weigel LM, Clewell DB, Gill SR, Clark NC, McDougal LK, Flannagan SE, et al. Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science. 2003;302(5650):1569–71.

    Article  CAS  PubMed  Google Scholar 

  41. Saravolatz LD, Pawlak J, Saravolatz SN, Johnson LB. In vitro activity of retapamulin against Staphylococcus aureus resistant to various antimicrobial agents. Antimicrob Agents Chemother. 2013;57(9):4547–50. doi:10.1128/AAC.00282-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hartman BJ, Tomasz A. Low-affinity penicillin-binding protein associated with beta-lactam resistance in Staphylococcus aureus. J Bacteriol. 1984;158(2):513–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Utsui Y, Yokota T. Role of an altered penicillin-binding protein in methicillin- and cephem-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1985;28(3):397–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Parvez MA, Shibata H, Nakano T, Niimi S, Fujii N, Arakaki N, et al. No relationship exists between PBP 2a amounts expressed in different MRSA strains obtained clinically and their beta-lactam MIC values. J Med Invest. 2008;55(3–4):246–53.

    Article  PubMed  Google Scholar 

  45. Garcia-Castellanos R, Mallorqui-Fernandez G, Marrero A, Potempa J, Coll M, Gomis-Ruth FX. On the transcriptional regulation of methicillin resistance: MecI repressor in complex with its operator. J Biol Chem. 2004;279(17):17888–96.

    Article  CAS  PubMed  Google Scholar 

  46. Amoroso A, Boudet J, Berzigotti S, Duval V, Teller N, Mengin-Lecreulx D, et al. A peptidoglycan fragment triggers beta-lactam resistance in Bacillus licheniformis. PLoS Pathog. 2012;8(3):e1002571. doi:10.1371/journal.ppat.1002571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ito T, Katayama Y, Asada K, Mori N, Tsutsumimoto K, Tiensasitorn C, et al. Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2001;45(5):1323–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ender M, McCallum N, Adhikari R, Berger-Bachi B. Fitness cost of SCCmec and methicillin resistance levels in Staphylococcus aureus. Antimicrob Agents Chemother. 2004;48(6):2295–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hiramatsu K, Cui L, Kuroda M, Ito T. The emergence and evolution of methicillin-resistant Staphylococcus aureus. Trends Microbiol. 2001;9(10):486–93.

    Article  CAS  PubMed  Google Scholar 

  50. Dordel J, Kim C, Chung M, Pardos de la Gandara M, Holden MT, Parkhill J, et al. Novel determinants of antibiotic resistance: identification of mutated loci in highly methicillin-resistant subpopulations of methicillin-resistant Staphylococcus aureus. MBio. 2014;5(2):e01000. doi:10.1128/mBio.01000-13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Pinho MG, de Lencastre H, Tomasz A. An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococci. Proc Natl Acad Sci U S A. 2001;98(19):10886–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pinho MG, Filipe SR, de Lencastre H, Tomasz A. Complementation of the essential peptidoglycan transpeptidase function of penicillin-binding protein 2 (PBP2) by the drug resistance protein PBP2A in Staphylococcus aureus. J Bacteriol. 2001;183(22):6525–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Navratna V, Nadig S, Sood V, Prasad K, Arakere G, Gopal B. Molecular basis for the role of Staphylococcus aureus penicillin binding protein 4 in antimicrobial resistance. J Bacteriol. 2010;192(1):134–44. doi:10.1128/JB.00822-09.

    Article  CAS  PubMed  Google Scholar 

  54. Leski TA, Tomasz A. Role of penicillin-binding protein 2 (PBP2) in the antibiotic susceptibility and cell wall cross-linking of Staphylococcus aureus: evidence for the cooperative functioning of PBP2, PBP4, and PBP2A. J Bacteriol. 2005;187(5):1815–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Memmi G, Filipe SR, Pinho MG, Fu Z, Cheung A. Staphylococcus aureus PBP4 is essential for beta-lactam resistance in community-acquired methicillin-resistant strains. Antimicrob Agents Chemother. 2008;52(11):3955–66. doi:10.1128/AAC.00049-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Farha MA, Leung A, Sewell EW, D’Elia MA, Allison SE, Ejim L, et al. Inhibition of WTA synthesis blocks the cooperative action of PBPs and sensitizes MRSA to beta-lactams. ACS Chem Biol. 2013;8(1):226–33. doi:10.1021/cb300413m.

    Article  CAS  PubMed  Google Scholar 

  57. Atilano ML, Pereira PM, Yates J, Reed P, Veiga H, Pinho MG, et al. Teichoic acids are temporal and spatial regulators of peptidoglycan cross-linking in Staphylococcus aureus. Proc Natl Acad Sci U S A. 2010;107(44):18991–6. doi:10.1073/pnas.1004304107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Brown S, Xia G, Luhachack LG, Campbell J, Meredith TC, Chen C, et al. Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids. Proc Natl Acad Sci U S A. 2012;109(46):18909–14. doi:10.1073/pnas.1209126109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. De Lencastre H, Wu SW, Pinho MG, Ludovice AM, Filipe S, Gardete S, et al. Antibiotic resistance as a stress response: complete sequencing of a large number of chromosomal loci in Staphylococcus aureus strain COL that impact on the expression of resistance to methicillin. Microb Drug Resist. 1999;5(3):163–75.

    Article  PubMed  Google Scholar 

  60. Henze U, Sidow T, Wecke J, Labischinski H, Berger-Bachi B. Influence of femB on methicillin resistance and peptidoglycan metabolism in Staphylococcus aureus. J Bacteriol. 1993;175(6):1612–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Stranden AM, Ehlert K, Labischinski H, Berger-Bachi B. Cell wall monoglycine cross-bridges and methicillin hypersusceptibility in a femAB null mutant of methicillin-resistant Staphylococcus aureus. J Bacteriol. 1997;179(1):9–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Arbeloa A, Hugonnet JE, Sentilhes AC, Josseaume N, Dubost L, Monsempes C, et al. Synthesis of mosaic peptidoglycan cross-bridges by hybrid peptidoglycan assembly pathways in gram-positive bacteria. J Biol Chem. 2004;279(40):41546–56.

    Article  CAS  PubMed  Google Scholar 

  63. Giannouli S, Labrou M, Kyritsis A, Ikonomidis A, Pournaras S, Stathopoulos C, et al. Detection of mutations in the FemXAB protein family in oxacillin-susceptible mecA-positive Staphylococcus aureus clinical isolates. J Antimicrob Chemother. 2010;65(4):626–33. doi:10.1093/jac/dkq039.

    Article  CAS  PubMed  Google Scholar 

  64. Komatsuzawa H, Ohta K, Labischinski H, Sugai M, Suginaka H. Characterization of fmtA, a gene that modulates the expression of methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 1999;43(9):2121–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Fan X, Liu Y, Smith D, Konermann L, Siu KW, Golemi-Kotra D. Diversity of penicillin-binding proteins. Resistance factor FmtA of Staphylococcus aureus. J Biol Chem. 2007;282(48):35143–52. doi:10.1074/jbc.M706296200.

    Article  CAS  PubMed  Google Scholar 

  66. Qamar A, Golemi-Kotra D. Dual roles of FmtA in Staphylococcus aureus cell wall biosynthesis and autolysis. Antimicrob Agents Chemother. 2012;56(7):3797–805. doi:10.1128/AAC.00187-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Antignac A, Tomasz A. Reconstruction of the phenotypes of methicillin-resistant Staphylococcus aureus by replacement of the staphylococcal cassette chromosome mec with a plasmid-borne copy of Staphylococcus sciuri pbpD gene. Antimicrob Agents Chemother. 2009;53(2):435–41. doi:10.1128/AAC.01099-08.

    Article  CAS  PubMed  Google Scholar 

  68. Couto I, Wu SW, Tomasz A, de Lencastre H. Development of methicillin resistance in clinical isolates of Staphylococcus sciuri by transcriptional activation of the mecA homologue native to s. J Bacteriol. 2003;185(2):645–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wu S, de Lencastre H, Tomasz A. Genetic organization of the mecA region in methicillin-susceptible and methicillin-resistant strains of Staphylococcus sciuri. J Bacteriol. 1998;180(2):236–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Tsubakishita S, Kuwahara-Arai K, Sasaki T, Hiramatsu K. Origin and molecular evolution of the determinant of methicillin resistance in staphylococci. Antimicrob Agents Chemother. 2010;54(10):4352–9. doi:10.1128/AAC.00356-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pierre J, Williamson R, Bornet M, Gutmann L. Presence of an additional penicillin-binding protein in methicillin-resistant Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus simulans with a low affinity for methicillin, cephalothin, and cefamandole. Antimicrob Agents Chemother. 1990;34(9):1691–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Harrison EM, Paterson GK, Holden MT, Larsen J, Stegger M, Larsen AR, et al. Whole genome sequencing identifies zoonotic transmission of MRSA isolates with the novel mecA homologue mecC. EMBO Mol Med. 2013;5(4):509–15. doi:10.1002/emmm.201202413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Shore AC, Deasy EC, Slickers P, Brennan G, O’Connell B, Monecke S, et al. Detection of staphylococcal cassette chromosome mec type XI carrying highly divergent mecA, mecI, mecR1, blaZ, and ccr genes in human clinical isolates of clonal complex 130 methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2011;55(8):3765–73. doi:10.1128/AAC.00187-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kim C, Milheirico C, Gardete S, Holmes MA, Holden MT, de Lencastre H, et al. Properties of a novel PBP2A protein homolog from Staphylococcus aureus strain LGA251 and its contribution to the beta-lactam-resistant phenotype. J Biol Chem. 2012;287(44):36854–63. doi:10.1074/jbc.M112.395962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chambers HF, Sachdeva MJ, Hackbarth CJ. Kinetics of penicillin binding to penicillin-binding proteins of Staphylococcus aureus. Biochem J. 1994;301(Pt 1):139–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Graves-Woodward K, Pratt RF. Reaction of soluble penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus with beta-lactams and acyclic substrates: kinetics in homogeneous solution. Biochem J. 1998;332(Pt 3):755–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lu WP, Sun Y, Bauer MD, Paule S, Koenigs PM, Kraft WG. Penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus: kinetic characterization of its interactions with beta-lactams using electrospray mass spectrometry. Biochemistry. 1999;38(20):6537–46.

    Article  CAS  PubMed  Google Scholar 

  78. Lu WP, Kincaid E, Sun Y, Bauer MD. Kinetics of beta-lactam interactions with penicillin-susceptible and -resistant penicillin-binding protein 2x proteins from Streptococcus pneumoniae. Involvement of acylation and deacylation in beta-lactam resistance. J Biol Chem. 2001;276(34):31494–501.

    Article  CAS  PubMed  Google Scholar 

  79. Mouz N, Gordon E, Di Guilmi AM, Petit I, Petillot Y, Dupont Y, et al. Identification of a structural determinant for resistance to beta-lactam antibiotics in Gram-positive bacteria. Proc Natl Acad Sci U S A. 1998;95(23):13403–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Fuda C, Suvorov M, Vakulenko SB, Mobashery S. The basis for resistance to beta-lactam antibiotics by penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus. J Biol Chem. 2004;279(39):40802–6.

    Article  CAS  PubMed  Google Scholar 

  81. Lim D, Strynadka NC. Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat Struct Biol. 2002;9(11):870–6.

    CAS  PubMed  Google Scholar 

  82. Beadle BM, Nicholas RA, Shoichet BK. Interaction energies between beta-lactam antibiotics and E. coli penicillin-binding protein 5 by reversible thermal denaturation. Protein Sci. 2001;10(6):1254–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Fuda C, Hesek D, Lee M, Heilmayer W, Novak R, Vakulenko SB, et al. Mechanistic basis for the action of new cephalosporin antibiotics effective against methicillin- and vancomycin-resistant Staphylococcus aureus. J Biol Chem. 2006;281(15):10035–41.

    Article  CAS  PubMed  Google Scholar 

  84. Fuda C, Hesek D, Lee M, Morio K, Nowak T, Mobashery S. Activation for catalysis of penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus by bacterial cell wall. J Am Chem Soc. 2005;127(7):2056–7.

    Article  CAS  PubMed  Google Scholar 

  85. Kosowska-Shick K, McGhee PL, Appelbaum PC. Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2010;54(5):1670–7. doi:10.1128/AAC.00019-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Otero LH, Rojas-Altuve A, Llarrull LI, Carrasco-Lopez C, Kumarasiri M, Lastochkin E, et al. How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function. Proc Natl Acad Sci U S A. 2013;110(42):16808–13. doi:10.1073/pnas.1300118110.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Fishovitz J, Rojas-Altuve A, Otero LH, Dawley M, Carrasco-Lopez C, Chang M, et al. Disruption of allosteric response as an unprecedented mechanism of resistance to antibiotics. J Am Chem Soc. 2014;136(28):9814–7. doi:10.1021/ja5030657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mendes RE, Tsakris A, Sader HS, Jones RN, Biek D, McGhee P, et al. Characterization of methicillin-resistant Staphylococcus aureus displaying increased MICs of ceftaroline. J Antimicrob Chemother. 2012;67(6):1321–4. doi:10.1093/jac/dks069.

    Article  CAS  PubMed  Google Scholar 

  89. Ba X, Harrison EM, Edwards GF, Holden MT, Larsen AR, Petersen A, et al. Novel mutations in penicillin-binding protein genes in clinical Staphylococcus aureus isolates that are methicillin resistant on susceptibility testing, but lack the mec gene. J Antimicrob Chemother. 2014;69(3):594–7. doi:10.1093/jac/dkt418.

    Article  CAS  PubMed  Google Scholar 

  90. Banerjee R, Gretes M, Harlem C, Basuino L, Chambers HF. A mecA-negative strain of methicillin-resistant Staphylococcus aureus with high-level beta-lactam resistance contains mutations in three genes. Antimicrob Agents Chemother. 2010;54(11):4900–2. doi:10.1128/AAC.00594-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Henze UU, Berger-Bachi B. Penicillin-binding protein 4 overproduction increases beta-lactam resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 1996;40(9):2121–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Tomasz A, Drugeon HB, de Lencastre HM, Jabes D, McDougall L, Bille J. New mechanism for methicillin resistance in Staphylococcus aureus: clinical isolates that lack the PBP 2a gene and contain normal penicillin-binding proteins with modified penicillin-binding capacity. Antimicrob Agents Chemother. 1989;33(11):1869–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hackbarth CJ, Kocagoz T, Kocagoz S, Chambers HF. Point mutations in Staphylococcus aureus PBP 2 gene affect penicillin-binding kinetics and are associated with resistance. Antimicrob Agents Chemother. 1995;39(1):103–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Contreras-Martel C, Amoroso A, Woon EC, Zervosen A, Inglis S, Martins A, et al. Structure-guided design of cell wall biosynthesis inhibitors that overcome beta-lactam resistance in Staphylococcus aureus (MRSA). ACS Chem Biol. 2011;6(9):943–51. doi:10.1021/cb2001846.

    Article  CAS  PubMed  Google Scholar 

  95. Turk S, Verlaine O, Gerards T, Zivec M, Humljan J, Sosic I, et al. New noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria. PLoS One. 2011;6(5):e19418. doi:10.1371/journal.pone.0019418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bernal P, Lemaire S, Pinho MG, Mobashery S, Hinds J, Taylor PW. Insertion of epicatechin gallate into the cytoplasmic membrane of methicillin-resistant Staphylococcus aureus disrupts penicillin-binding protein (PBP) 2a-mediated beta-lactam resistance by delocalizing PBP2. J Biol Chem. 2010;285(31):24055–65. doi:10.1074/jbc.M110.114793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yao X, Lu CD. A PBP 2 mutant devoid of the transpeptidase domain abolishes spermine-beta-lactam synergy in Staphylococcus aureus Mu50. Antimicrob Agents Chemother. 2012;56(1):83–91. doi:10.1128/AAC.05415-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Perez JL, Riera L, Valls F, Berrocal CI, Berrocal L. A comparison of the in-vitro activity of seventeen antibiotics against Streptococcus faecalis. J Antimicrob Chemother. 1987;20(3):357–62.

    Article  CAS  PubMed  Google Scholar 

  99. Moellering Jr RC, Korzeniowski OM, Sande MA, Wennersten CB. Species-specific resistance to antimocrobial synergism in Streptococcus faecium and Streptococcus faecalis. J Infect Dis. 1979;140(2):203–8.

    Article  CAS  PubMed  Google Scholar 

  100. Arbeloa A, Segal H, Hugonnet JE, Josseaume N, Dubost L, Brouard JP, et al. Role of class A penicillin-binding proteins in PBP5-mediated beta-lactam resistance in Enterococcus faecalis. J Bacteriol. 2004;186(5):1221–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Fontana R, Cerini R, Longoni P, Grossato A, Canepari P. Identification of a streptococcal penicillin-binding protein that reacts very slowly with penicillin. J Bacteriol. 1983;155(3):1343–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Fontana R, Grossato A, Rossi L, Cheng YR, Satta G. Transition from resistance to hypersusceptibility to beta-lactam antibiotics associated with loss of a low-affinity penicillin-binding protein in a Streptococcus faecium mutant highly resistant to penicillin. Antimicrob Agents Chemother. 1985;28(5):678–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lleo MM, Canepari P, Cornaglia G, Fontana R, Satta G. Bacteriostatic and bactericidal activities of beta-lactams against Streptococcus (Enterococcus) faecium are associated with saturation of different penicillin-binding proteins. Antimicrob Agents Chemother. 1987;31(10):1618–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sifaoui F, Arthur M, Rice L, Gutmann L. Role of penicillin-binding protein 5 in expression of ampicillin resistance and peptidoglycan structure in Enterococcus faecium. Antimicrob Agents Chemother. 2001;45(9):2594–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Williamson R, le Bouguenec C, Gutmann L, Horaud T. One or two low affinity penicillin-binding proteins may be responsible for the range of susceptibility of Enterococcus faecium to benzylpenicillin. J Gen Microbiol. 1985;131(Pt 8):1933–40.

    CAS  PubMed  Google Scholar 

  106. Duez C, Zorzi W, Sapunaric F, Amoroso A, Thamm I, Coyette J. The penicillin resistance of Enterococcus faecalis JH2-2r results from an overproduction of the low-affinity penicillin-binding protein PBP4 and does not involve a psr-like gene. Microbiology. 2001;147(Pt 9):2561–9.

    Article  CAS  PubMed  Google Scholar 

  107. Fontana R, Aldegheri M, Ligozzi M, Lopez H, Sucari A, Satta G. Overproduction of a low-affinity penicillin-binding protein and high-level ampicillin resistance in Enterococcus faecium. Antimicrob Agents Chemother. 1994;38(9):1980–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hsieh SE, Hsu LL, Hsu WH, Chen CY, Chen HJ, Liao CT. Importance of amino acid alterations and expression of penicillin-binding protein 5 to ampicillin resistance of Enterococcus faecium in Taiwan. Int J Antimicrob Agents. 2006;28(6):514–9. doi:10.1016/j.ijantimicag.2006.07.027.

    Article  CAS  PubMed  Google Scholar 

  109. Klare I, Rodloff AC, Wagner J, Witte W, Hakenbeck R. Overproduction of a penicillin-binding protein is not the only mechanism of penicillin resistance in Enterococcus faecium. Antimicrob Agents Chemother. 1992;36(4):783–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Rybkine T, Mainardi JL, Sougakoff W, Collatz E, Gutmann L. Penicillin-binding protein 5 sequence alterations in clinical isolates of Enterococcus faecium with different levels of beta-lactam resistance. J Infect Dis. 1998;178(1):159–63.

    Article  CAS  PubMed  Google Scholar 

  111. Zorzi W, Zhou XY, Dardenne O, Lamotte J, Raze D, Pierre J, et al. Structure of the low-affinity penicillin-binding protein 5 PBP5fm in wild-type and highly penicillin-resistant strains of Enterococcus faecium. J Bacteriol. 1996;178(16):4948–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rice LB, Carias LL, Rudin S, Lakticova V, Wood A, Hutton-Thomas R. Enterococcus faecium low-affinity pbp5 is a transferable determinant. Antimicrob Agents Chemother. 2005;49(12):5007–12. doi:10.1128/AAC.49.12.5007-5012.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Piras G, el Kharroubi A, van Beeumen J, Coeme E, Coyette J, Ghuysen JM. Characterization of an Enterococcus hirae penicillin-binding protein 3 with low penicillin affinity. J Bacteriol. 1990;172(12):6856–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Piras G, Raze D, el Kharroubi A, Hastir D, Englebert S, Coyette J, et al. Cloning and sequencing of the low-affinity penicillin-binding protein 3r-encoding gene of Enterococcus hirae S185: modular design and structural organization of the protein. J Bacteriol. 1993;175(10):2844–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ligozzi M, Pittaluga F, Fontana R. Modification of penicillin-binding protein 5 associated with high-level ampicillin resistance in Enterococcus faecium. Antimicrob Agents Chemother. 1996;40(2):354–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Galloway-Pena JR, Rice LB, Murray BE. Analysis of PBP5 of early U.S. isolates of Enterococcus faecium: sequence variation alone does not explain increasing ampicillin resistance over time. Antimicrob Agents Chemother. 2011;55(7):3272–7. doi:10.1128/AAC.00099-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Jureen R, Mohn SC, Harthug S, Haarr L, Langeland N. Role of penicillin-binding protein 5 C-terminal amino acid substitutions in conferring ampicillin resistance in Norwegian clinical strains of Enterococcus faecium. APMIS. 2004;112(4–5):291–8.

    Article  CAS  PubMed  Google Scholar 

  118. Rice LB, Bellais S, Carias LL, Hutton-Thomas R, Bonomo RA, Caspers P, et al. Impact of specific pbp5 mutations on expression of beta-lactam resistance in Enterococcus faecium. Antimicrob Agents Chemother. 2004;48(8):3028–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sauvage E, Kerff F, Fonze E, Herman R, Schoot B, Marquette JP, et al. The 2.4-A crystal structure of the penicillin-resistant penicillin-binding protein PBP5fm from Enterococcus faecium in complex with benzylpenicillin. Cell Mol Life Sci. 2002;59(7):1223–32.

    Article  CAS  PubMed  Google Scholar 

  120. Hujer AM, Kania M, Gerken T, Anderson VE, Buynak JD, Ge X, et al. Structure-activity relationships of different beta-lactam antibiotics against a soluble form of Enterococcus faecium PBP5, a type II bacterial transpeptidase. Antimicrob Agents Chemother. 2005;49(2):612–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Rice LB, Carias LL, Rudin S, Hutton R, Marshall S, Hassan M, et al. Role of class A penicillin-binding proteins in the expression of beta-lactam resistance in Enterococcus faecium. J Bacteriol. 2009;191(11):3649–56. doi:10.1128/JB.01834-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ligozzi M, Pittaluga F, Fontana R. Identification of a genetic element (psr) which negatively controls expression of Enterococcus hirae penicillin-binding protein 5. J Bacteriol. 1993;175(7):2046–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sapunaric F, Franssen C, Stefanic P, Amoroso A, Dardenne O, Coyette J. Redefining the role of psr in beta-lactam resistance and cell autolysis of Enterococcus hirae. J Bacteriol. 2003;185(20):5925–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Rice LB, Carias LL, Hutton-Thomas R, Sifaoui F, Gutmann L, Rudin SD. Penicillin-binding protein 5 and expression of ampicillin resistance in Enterococcus faecium. Antimicrob Agents Chemother. 2001;45(5):1480–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ono S, Muratani T, Matsumoto T. Mechanisms of resistance to imipenem and ampicillin in Enterococcus faecalis. Antimicrob Agents Chemother. 2005;49(7):2954–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Murray BE. Beta-lactamase-producing enterococci. Antimicrob Agents Chemother. 1992;36(11):2355–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Mainardi JL, Fourgeaud M, Hugonnet JE, Dubost L, Brouard JP, Ouazzani J, et al. A novel peptidoglycan cross-linking enzyme for a beta-lactam-resistant transpeptidation pathway. J Biol Chem. 2005;280(46):38146–52.

    Article  CAS  PubMed  Google Scholar 

  128. Mainardi JL, Legrand R, Arthur M, Schoot B, van Heijenoort J, Gutmann L. Novel mechanism of beta-lactam resistance due to bypass of DD-transpeptidation in Enterococcus faecium. J Biol Chem. 2000;275(22):16490–6.

    Article  CAS  PubMed  Google Scholar 

  129. Mainardi JL, Morel V, Fourgeaud M, Cremniter J, Blanot D, Legrand R, et al. Balance between two transpeptidation mechanisms determines the expression of beta-lactam resistance in Enterococcus faecium. J Biol Chem. 2002;277(39):35801–7.

    Article  CAS  PubMed  Google Scholar 

  130. Sacco E, Hugonnet JE, Josseaume N, Cremniter J, Dubost L, Marie A, et al. Activation of the L, D-transpeptidation peptidoglycan cross-linking pathway by a metallo-D,D-carboxypeptidase in Enterococcus faecium. Mol Microbiol. 2010;75(4):874–85. doi:10.1111/j.1365-2958.2009.07014.x.

    Article  CAS  PubMed  Google Scholar 

  131. Hakenbeck R, Tarpay M, Tomasz A. Multiple changes of penicillin-binding proteins in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1980;17(3):364–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zighelboim S, Tomasz A. Penicillin-binding proteins of multiply antibiotic-resistant South African strains of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1980;17(3):434–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Laible G, Spratt BG, Hakenbeck R. Interspecies recombinational events during the evolution of altered PBP 2x genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Mol Microbiol. 1991;5(8):1993–2002.

    Article  CAS  PubMed  Google Scholar 

  134. Dowson CG, Hutchison A, Brannigan JA, George RC, Hansman D, Linares J, et al. Horizontal transfer of penicillin-binding protein genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Proc Natl Acad Sci U S A. 1989;86(22):8842–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Martin C, Sibold C, Hakenbeck R. Relatedness of penicillin-binding protein 1a genes from different clones of penicillin-resistant Streptococcus pneumoniae isolated in South Africa and Spain. Embo J. 1992;11(11):3831–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Claverys JP, Prudhomme M, Mortier-Barriere I, Martin B. Adaptation to the environment: Streptococcus pneumoniae, a paradigm for recombination-mediated genetic plasticity? Mol Microbiol. 2000;35(2):251–9.

    Article  CAS  PubMed  Google Scholar 

  137. Smith AM, Klugman KP. Alterations in penicillin-binding protein 2B from penicillin-resistant wild-type strains of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1995;39(4):859–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sibold C, Henrichsen J, Konig A, Martin C, Chalkley L, Hakenbeck R. Mosaic pbpX genes of major clones of penicillin-resistant Streptococcus pneumoniae have evolved from pbpX genes of a penicillin-sensitive Streptococcus oralis. Mol Microbiol. 1994;12(6):1013–23.

    Article  CAS  PubMed  Google Scholar 

  139. Chi F, Nolte O, Bergmann C, Ip M, Hakenbeck R. Crossing the barrier: Evolution and spread of a major class of mosaic pbp2x in Streptococcus pneumoniae, S. mitis and S. oralis. Int J Med Microbiol. 2007;297(7–8):503–12.

    Article  CAS  PubMed  Google Scholar 

  140. Dowson CG, Hutchison A, Woodford N, Johnson AP, George RC, Spratt BG. Penicillin-resistant viridans streptococci have obtained altered penicillin-binding protein genes from penicillin-resistant strains of Streptococcus pneumoniae. Proc Natl Acad Sci U S A. 1990;87(15):5858–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Reichmann P, Konig A, Linares J, Alcaide F, Tenover FC, McDougal L, et al. A global gene pool for high-level cephalosporin resistance in commensal Streptococcus species and Streptococcus pneumoniae. J Infect Dis. 1997;176(4):1001–12.

    Article  CAS  PubMed  Google Scholar 

  142. Coffey TJ, Dowson CG, Daniels M, Zhou J, Martin C, Spratt BG, et al. Horizontal transfer of multiple penicillin-binding protein genes, and capsular biosynthetic genes, in natural populations of Streptococcus pneumoniae. Mol Microbiol. 1991;5(9):2255–60.

    Article  CAS  PubMed  Google Scholar 

  143. Zhou J, Enright MC, Spratt BG. Identification of the major Spanish clones of penicillin-resistant pneumococci via the Internet using multilocus sequence typing. J Clin Microbiol. 2000;38(3):977–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. McGee L, McDougal L, Zhou J, Spratt BG, Tenover FC, George R, et al. Nomenclature of major antimicrobial-resistant clones of Streptococcus pneumoniae defined by the pneumococcal molecular epidemiology network. J Clin Microbiol. 2001;39(7):2565–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Stanhope MJ, Walsh SL, Becker JA, Miller LA, Lefebure T, Lang P, et al. The relative frequency of intraspecific lateral gene transfer of penicillin binding proteins 1a, 2b, and 2x, in amoxicillin resistant Streptococcus pneumoniae. Infect Genet Evol. 2007;7(4):520–34. doi:10.1016/j.meegid.2007.03.004.

    Article  CAS  PubMed  Google Scholar 

  146. Grebe T, Hakenbeck R. Penicillin-binding proteins 2b and 2x of Streptococcus pneumoniae are primary resistance determinants for different classes of beta-lactam antibiotics. Antimicrob Agents Chemother. 1996;40(4):829–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Krauss J, van der Linden M, Grebe T, Hakenbeck R. Penicillin-binding proteins 2x and 2b as primary PBP targets in Streptococcus pneumoniae. Microb Drug Resist. 1996;2(2):183–6.

    Article  CAS  PubMed  Google Scholar 

  148. Sifaoui F, Kitzis MD, Gutmann L. In vitro selection of one-step mutants of Streptococcus pneumoniae resistant to different oral beta-lactam antibiotics is associated with alterations of PBP2x. Antimicrob Agents Chemother. 1996;40(1):152–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Coffey TJ, Daniels M, McDougal LK, Dowson CG, Tenover FC, Spratt BG. Genetic analysis of clinical isolates of Streptococcus pneumoniae with high-level resistance to expanded-spectrum cephalosporins. Antimicrob Agents Chemother. 1995;39(6):1306–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Asahi Y, Takeuchi Y, Ubukata K. Diversity of substitutions within or adjacent to conserved amino acid motifs of penicillin-binding protein 2X in cephalosporin-resistant Streptococcus pneumoniae isolates. Antimicrob Agents Chemother. 1999;43(5):1252–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Laible G, Hakenbeck R. Penicillin-binding proteins in beta-lactam-resistant laboratory mutants of Streptococcus pneumoniae. Mol Microbiol. 1987;1(3):355–63.

    Article  CAS  PubMed  Google Scholar 

  152. Hakenbeck R, Tornette S, Adkinson NF. Interaction of non-lytic beta-lactams with penicillin-binding proteins in Streptococcus pneumoniae. J Gen Microbiol. 1987;133(Pt 3):755–60.

    CAS  PubMed  Google Scholar 

  153. Maurer P, Koch B, Zerfass I, Krauss J, van der Linden M, Frere JM, et al. Penicillin-binding protein 2x of Streptococcus pneumoniae: three new mutational pathways for remodelling an essential enzyme into a resistance determinant. J Mol Biol. 2008;376(5):1403–16. doi:10.1016/j.jmb.2007.12.058.

    Article  CAS  PubMed  Google Scholar 

  154. Chesnel L, Pernot L, Lemaire D, Champelovier D, Croize J, Dideberg O, et al. The structural modifications induced by the M339F substitution in PBP2x from Streptococcus pneumoniae further decreases the susceptibility to beta-lactams of resistant strains. J Biol Chem. 2003;278(45):44448–56.

    Article  CAS  PubMed  Google Scholar 

  155. Dowson CG, Hutchison A, Spratt BG. Extensive re-modelling of the transpeptidase domain of penicillin-binding protein 2B of a penicillin-resistant South African isolate of Streptococcus pneumoniae. Mol Microbiol. 1989;3(1):95–102.

    Article  CAS  PubMed  Google Scholar 

  156. du Plessis M, Bingen E, Klugman KP. Analysis of penicillin-binding protein genes of clinical isolates of Streptococcus pneumoniae with reduced susceptibility to amoxicillin. Antimicrob Agents Chemother. 2002;46(8):2349–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Pernot L, Chesnel L, Le Gouellec A, Croize J, Vernet T, Dideberg O, et al. A PBP2x from a clinical isolate of Streptococcus pneumoniae exhibits an alternative mechanism for reduction of susceptibility to beta-lactam antibiotics. J Biol Chem. 2004;279(16):16463–70.

    Article  CAS  PubMed  Google Scholar 

  158. Reichmann P, Konig A, Marton A, Hakenbeck R. Penicillin-binding proteins as resistance determinants in clinical isolates of Streptococcus pneumoniae. Microb Drug Resist. 1996;2(2):177–81.

    Article  CAS  PubMed  Google Scholar 

  159. Smith AM, Klugman KP. Alterations in PBP 1A essential-for high-level penicillin resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother. 1998;42(6):1329–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Pagliero E, Chesnel L, Hopkins J, Croize J, Dideberg O, Vernet T, et al. Biochemical characterization of Streptococcus pneumoniae penicillin-binding protein 2b and its implication in beta-lactam resistance. Antimicrob Agents Chemother. 2004;48(5):1848–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Barcus VA, Ghanekar K, Yeo M, Coffey TJ, Dowson CG. Genetics of high level penicillin resistance in clinical isolates of Streptococcus pneumoniae. FEMS Microbiol Lett. 1995;126(3):299–303.

    Article  CAS  PubMed  Google Scholar 

  162. Munoz R, Dowson CG, Daniels M, Coffey TJ, Martin C, Hakenbeck R, et al. Genetics of resistance to third-generation cephalosporins in clinical isolates of Streptococcus pneumoniae. Mol Microbiol. 1992;6(17):2461–5.

    Article  CAS  PubMed  Google Scholar 

  163. Sanbongi Y, Ida T, Ishikawa M, Osaki Y, Kataoka H, Suzuki T, et al. Complete sequences of six penicillin-binding protein genes from 40 Streptococcus pneumoniae clinical isolates collected in Japan. Antimicrob Agents Chemother. 2004;48(6):2244–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Ubukata K, Chiba N, Hasegawa K, Kobayashi R, Iwata S, Sunakawa K. Antibiotic susceptibility in relation to penicillin-binding protein genes and serotype distribution of Streptococcus pneumoniae strains responsible for meningitis in Japan, 1999 to 2002. Antimicrob Agents Chemother. 2004;48(5):1488–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ferroni A, Berche P. Alterations to penicillin-binding proteins 1A, 2B and 2X amongst penicillin-resistant clinical isolates of Streptococcus pneumoniae serotype 23F from the nasopharyngeal flora of children. J Med Microbiol. 2001;50(9):828–32.

    Article  CAS  PubMed  Google Scholar 

  166. Izdebski R, Rutschmann J, Fiett J, Sadowy E, Gniadkowski M, Hryniewicz W, et al. Highly variable penicillin resistance determinants PBP 2x, PBP 2b, and PBP 1a in isolates of two Streptococcus pneumoniae clonal groups, Poland 23F-16 and Poland 6B-20. Antimicrob Agents Chemother. 2008;52(3):1021–7. doi:10.1128/AAC.01082-07.

    Article  CAS  PubMed  Google Scholar 

  167. Nagai K, Davies TA, Jacobs MR, Appelbaum PC. Effects of amino acid alterations in penicillin-binding proteins (PBPs) 1a, 2b, and 2x on PBP affinities of penicillin, ampicillin, amoxicillin, cefditoren, cefuroxime, cefprozil, and cefaclor in 18 clinical isolates of penicillin-susceptible, -intermediate, and -resistant pneumococci. Antimicrob Agents Chemother. 2002;46(5):1273–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Nichol KA, Zhanel GG, Hoban DJ. Penicillin-binding protein 1A, 2B, and 2X alterations in Canadian isolates of penicillin-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother. 2002;46(10):3261–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Overweg K, Bogaert D, Sluijter M, de Groot R, Hermans PW. Molecular characteristics of penicillin-binding protein genes of penicillin-nonsusceptible Streptococcus pneumoniae isolated in the Netherlands. Microb Drug Resist. 2001;7(4):323–34.

    Article  CAS  PubMed  Google Scholar 

  170. Granger D, Boily-Larouche G, Turgeon P, Weiss K, Roger M. Molecular characteristics of pbp1a and pbp2b in clinical Streptococcus pneumoniae isolates in Quebec, Canada. J Antimicrob Chemother. 2006;57(1):61–70. doi:10.1093/jac/dki401.

    Article  CAS  PubMed  Google Scholar 

  171. McDougal LK, Rasheed JK, Biddle JW, Tenover FC. Identification of multiple clones of extended-spectrum cephalosporin-resistant Streptococcus pneumoniae isolates in the United States. Antimicrob Agents Chemother. 1995;39(10):2282–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Smith AM, Klugman KP. Alterations in MurM, a cell wall muropeptide branching enzyme, increase high-level penicillin and cephalosporin resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45(8):2393–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Cafini F, Aguilar L, Sevillano D, Gimenez MJ, Alou L, Fenoll A, et al. Decrease in bacterial load versus resistance selection of pneumococcal subpopulations by beta-lactam physiological concentrations over time: an in vitro pharmacodynamic simulation. Microb Drug Resist. 2008;14(1):13–21. doi:10.1089/mdr.2008.0783.

    Article  CAS  PubMed  Google Scholar 

  174. Coffey TJ, Daniels M, Enright MC, Spratt BG. Serotype 14 variants of the Spanish penicillin-resistant serotype 9V clone of Streptococcus pneumoniae arose by large recombinational replacements of the cpsA-pbp1a region. Microbiology. 1999;145(Pt 8):2023–31.

    Article  CAS  PubMed  Google Scholar 

  175. Enright MC, Spratt BG. Extensive variation in the ddl gene of penicillin-resistant Streptococcus pneumoniae results from a hitchhiking effect driven by the penicillin-binding protein 2b gene. Mol Biol Evol. 1999;16(12):1687–95.

    Article  CAS  PubMed  Google Scholar 

  176. Stanhope MJ, Lefebure T, Walsh SL, Becker JA, Lang P, Pavinski Bitar PD, et al. Positive selection in penicillin-binding proteins 1a, 2b, and 2x from Streptococcus pneumoniae and its correlation with amoxicillin resistance development. Infect Genet Evol. 2008;8(3):331–9. doi:10.1016/j.meegid.2008.02.001.

    Article  CAS  PubMed  Google Scholar 

  177. Chesnel L, Zapun A, Mouz N, Dideberg O, Vernet T. Increase of the deacylation rate of PBP2x from Streptococcus pneumoniae by single point mutations mimicking the class A beta-lactamases. Eur J Biochem. 2002;269(6):1678–83.

    Article  CAS  PubMed  Google Scholar 

  178. Di Guilmi AM, Mouz N, Petillot Y, Forest E, Dideberg O, Vernet T. Deacylation kinetics analysis of Streptococcus pneumoniae penicillin-binding protein 2x mutants resistant to beta-lactam antibiotics using electrospray ionization- mass spectrometry. Anal Biochem. 2000;284(2):240–6.

    Article  PubMed  CAS  Google Scholar 

  179. Jamin M, Damblon C, Millier S, Hakenbeck R, Frere JM. Penicillin-binding protein 2x of Streptococcus pneumoniae: enzymic activities and interactions with beta-lactams. Biochem J. 1993;292(Pt 3):735–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Thomas B, Wang Y, Stein RL. Kinetic and mechanistic studies of penicillin-binding protein 2x from Streptococcus pneumoniae. Biochemistry. 2001;40(51):15811–23.

    Article  CAS  PubMed  Google Scholar 

  181. Gordon E, Mouz N, Duee E, Dideberg O. The crystal structure of the penicillin-binding protein 2x from Streptococcus pneumoniae and its acyl-enzyme form: implication in drug resistance. J Mol Biol. 2000;299(2):477–85.

    Article  CAS  PubMed  Google Scholar 

  182. Dessen A, Mouz N, Gordon E, Hopkins J, Dideberg O. Crystal structure of PBP2x from a highly penicillin-resistant Streptococcus pneumoniae clinical isolate: a mosaic framework containing 83 mutations. J Biol Chem. 2001;276(48):45106–12.

    Article  CAS  PubMed  Google Scholar 

  183. Morlot C, Bayle L, Jacq M, Fleurie A, Tourcier G, Galisson F, et al. Interaction of Penicillin-Binding Protein 2x and Ser/Thr protein kinase StkP, two key players in Streptococcus pneumoniae R6 morphogenesis. Mol Microbiol. 2013. doi:10.1111/mmi.12348.

    PubMed Central  Google Scholar 

  184. Peters K, Schweizer I, Beilharz K, Stahlmann C, Veening JW, Hakenbeck R, et al. Streptococcus pneumoniae PBP2x mid-cell localization requires the C-terminal PASTA domains and is essential for cell shape maintenance. Mol Microbiol. 2014;92(4):733–55. doi:10.1111/mmi.12588.

    Article  CAS  PubMed  Google Scholar 

  185. Granger D, Boily-Larouche G, Turgeon P, Weiss K, Roger M. Genetic analysis of pbp2x in clinical Streptococcus pneumoniae isolates in Quebec, Canada. J Antimicrob Chemother. 2005;55(6):832–9. doi:10.1093/jac/dki118.

    Article  CAS  PubMed  Google Scholar 

  186. Mouz N, Di Guilmi AM, Gordon E, Hakenbeck R, Dideberg O, Vernet T. Mutations in the active site of penicillin-binding protein PBP2x from Streptococcus pneumoniae. Role in the specificity for beta-lactam antibiotics. J Biol Chem. 1999;274(27):19175–80.

    Article  CAS  PubMed  Google Scholar 

  187. Davies TA, Flamm RK, Lynch AS. Activity of ceftobiprole against Streptococcus pneumoniae isolates exhibiting high-level resistance to ceftriaxone. Int J Antimicrob Agents. 2012;39(6):534–8. doi:10.1016/j.ijantimicag.2012.02.016.

    Article  CAS  PubMed  Google Scholar 

  188. Soriano F, Cafini F, Aguilar L, Tarrago D, Alou L, Gimenez MJ, et al. Breakthrough in penicillin resistance? Streptococcus pneumoniae isolates with penicillin/cefotaxime MICs of 16 mg/L and their genotypic and geographical relatedness. J Antimicrob Chemother. 2008;62(6):1234–40. doi:10.1093/jac/dkn392.

    Article  CAS  PubMed  Google Scholar 

  189. Carapito R, Chesnel L, Vernet T, Zapun A. Pneumococcal beta-lactam resistance due to a conformational change in penicillin-binding protein 2x. J Biol Chem. 2006;281(3):1771–7.

    Article  CAS  PubMed  Google Scholar 

  190. Smith AM, Klugman KP. Amino acid mutations essential to production of an altered PBP 2X conferring high-level beta-lactam resistance in a clinical isolate of Streptococcus pneumoniae. Antimicrob Agents Chemother. 2005;49(11):4622–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Contreras-Martel C, Dahout-Gonzalez C, Martins Ados S, Kotnik M, Dessen A. PBP active site flexibility as the key mechanism for beta-lactam resistance in pneumococci. J Mol Biol. 2009;387(4):899–909. doi:10.1016/j.jmb.2009.02.024.

    Article  CAS  PubMed  Google Scholar 

  192. Yamane A, Nakano H, Asahi Y, Ubukata K, Konno M. Directly repeated insertion of 9-nucleotide sequence detected in penicillin-binding protein 2B gene of penicillin-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother. 1996;40(5):1257–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Cafini F, del Campo R, Alou L, Sevillano D, Morosini MI, Baquero F, et al. Alterations of the penicillin-binding proteins and murM alleles of clinical Streptococcus pneumoniae isolates with high-level resistance to amoxicillin in Spain. J Antimicrob Chemother. 2006;57(2):224–9. doi:10.1093/jac/dki442.

    Article  CAS  PubMed  Google Scholar 

  194. Kosowska K, Jacobs MR, Bajaksouzian S, Koeth L, Appelbaum PC. Alterations of penicillin-binding proteins 1A, 2X, and 2B in Streptococcus pneumoniae isolates for which amoxicillin MICs are higher than penicillin MICs. Antimicrob Agents Chemother. 2004;48(10):4020–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Song JH, Yang JW, Jin JH, Kim SW, Kim CK, Lee H, et al. Molecular characterization of multidrug-resistant Streptococcus pneumoniae isolates in Korea. The Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study Group. J Clin Microbiol. 2000;38(4):1641–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Kell CM, Jordens JZ, Daniels M, Coffey TJ, Bates J, Paul J, et al. Molecular epidemiology of penicillin-resistant pneumococci isolated in Nairobi, Kenya. Infect Immun. 1993;61(10):4382–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Contreras-Martel C, Job V, Di Guilmi AM, Vernet T, Dideberg O, Dessen A. Crystal structure of penicillin-binding protein 1a (PBP1a) reveals a mutational hotspot implicated in beta-lactam resistance in Streptococcus pneumoniae. J Mol Biol. 2006;355(4):684–96.

    Article  CAS  PubMed  Google Scholar 

  198. Job V, Carapito R, Vernet T, Dessen A, Zapun A. Common alterations in PBP1a from resistant Streptococcus pneumoniae decrease its reactivity toward beta-lactams: structural insights. J Biol Chem. 2008;283(8):4886–94. doi:10.1074/jbc.M706181200.

    Article  CAS  PubMed  Google Scholar 

  199. Di Guilmi AM, Mouz N, Andrieu JP, Hoskins J, Jaskunas SR, Gagnon J, et al. Identification, purification, and characterization of transpeptidase and glycosyltransferase domains of Streptococcus pneumoniae penicillin-binding protein 1a. J Bacteriol. 1998;180(21):5652–9.

    PubMed  PubMed Central  Google Scholar 

  200. Asahi Y, Ubukata K. Association of a thr-371 substitution in a conserved amino acid motif of penicillin-binding protein 1A with penicillin resistance of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1998;42(9):2267–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Smith AM, Klugman KP. Site-specific mutagenesis analysis of PBP 1A from a penicillin-cephalosporin-resistant pneumococcal isolate. Antimicrob Agents Chemother. 2003;47(1):387–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Hakenbeck R, Konig A, Kern I, van der Linden M, Keck W, Billot-Klein D, et al. Acquisition of five high-Mr penicillin-binding protein variants during transfer of high-level beta-lactam resistance from Streptococcus mitis to Streptococcus pneumoniae. J Bacteriol. 1998;180(7):1831–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Du Plessis M, Smith AM, Klugman KP. Analysis of penicillin-binding protein lb and 2a genes from Streptococcus pneumoniae. Microb Drug Resist. 2000;6(2):127–31.

    Article  PubMed  Google Scholar 

  204. Chesnel L, Carapito R, Croize J, Dideberg O, Vernet T, Zapun A. Identical penicillin-binding domains in penicillin-binding proteins of Streptococcus pneumoniae clinical isolates with different levels of beta-lactam resistance. Antimicrob Agents Chemother. 2005;49(7):2895–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Smith AM, Feldman C, Massidda O, McCarthy K, Ndiweni D, Klugman KP. Altered PBP 2A and its role in the development of penicillin, cefotaxime, and ceftriaxone resistance in a clinical isolate of Streptococcus pneumoniae. Antimicrob Agents Chemother. 2005;49(5):2002–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Hoskins J, Matsushima P, Mullen DL, Tang J, Zhao G, Meier TI, et al. Gene disruption studies of penicillin-binding proteins 1a, 1b, and 2a in Streptococcus pneumoniae. J Bacteriol. 1999;181(20):6552–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Schuster C, Dobrinski B, Hakenbeck R. Unusual septum formation in Streptococcus pneumoniae mutants with an alteration in the D, D-carboxypeptidase penicillin-binding protein 3. J Bacteriol. 1990;172(11):6499–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Paik J, Kern I, Lurz R, Hakenbeck R. Mutational analysis of the Streptococcus pneumoniae bimodular class A penicillin-binding proteins. J Bacteriol. 1999;181(12):3852–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Zhao G, Meier TI, Hoskins J, McAllister KA. Identification and characterization of the penicillin-binding protein 2a of Streptococcus pneumoniae and its possible role in resistance to beta-lactam antibiotics. Antimicrob Agents Chemother. 2000;44(6):1745–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Kempf M, Baraduc R, Bonnabau H, Brun M, Chabanon G, Chardon H, et al. Epidemiology and antimicrobial resistance of Streptococcus pneumoniae in France in 2007: data from the pneumococcus surveillance network. Microb Drug Resist. 2011;17(1):31–6. doi:10.1089/mdr.2010.0031.

    Article  PubMed  Google Scholar 

  211. Trzcinski K, Thompson CM, Gilbey AM, Dowson CG, Lipsitch M. Incremental increase in fitness cost with increased beta -lactam resistance in pneumococci evaluated by competition in an infant rat nasal colonization model. J Infect Dis. 2006;193(9):1296–303. doi:10.1086/501367.

    Article  CAS  PubMed  Google Scholar 

  212. Albarracin Orio AG, Pinas GE, Cortes PR, Cian MB, Echenique J. Compensatory evolution of pbp mutations restores the fitness cost imposed by beta-lactam resistance in Streptococcus pneumoniae. PLoS Pathog. 2011;7(2):e1002000. doi:10.1371/journal.ppat.1002000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Maurer P, Todorova K, Sauerbier J, Hakenbeck R. Mutations in Streptococcus pneumoniae penicillin-binding protein 2x: importance of the C-terminal penicillin-binding protein and serine/threonine kinase-associated domains for beta-lactam binding. Microb Drug Resist. 2012;18(3):314–21. doi:10.1089/mdr.2012.0022.

    Article  CAS  PubMed  Google Scholar 

  214. Yeats C, Finn RD, Bateman A. The PASTA domain: a beta-lactam-binding domain. Trends Biochem Sci. 2002;27(9):438.

    Article  CAS  PubMed  Google Scholar 

  215. Garcia-Bustos J, Tomasz A. A biological price of antibiotic resistance: major changes in the peptidoglycan structure of penicillin-resistant pneumococci. Proc Natl Acad Sci U S A. 1990;87(14):5415–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Severin A, Figueiredo AM, Tomasz A. Separation of abnormal cell wall composition from penicillin resistance through genetic transformation of Streptococcus pneumoniae. J Bacteriol. 1996;178(7):1788–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Filipe SR, Tomasz A. Inhibition of the expression of penicillin resistance in Streptococcus pneumoniae by inactivation of cell wall muropeptide branching genes. Proc Natl Acad Sci U S A. 2000;97(9):4891–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Weber B, Ehlert K, Diehl A, Reichmann P, Labischinski H, Hakenbeck R. The fib locus in Streptococcus pneumoniae is required for peptidoglycan crosslinking and PBP-mediated beta-lactam resistance. FEMS Microbiol Lett. 2000;188(1):81–5.

    CAS  PubMed  Google Scholar 

  219. Mascher T, Heintz M, Zahner D, Merai M, Hakenbeck R. The CiaRH system of Streptococcus pneumoniae prevents lysis during stress induced by treatment with cell wall inhibitors and by mutations in pbp2x involved in beta-lactam resistance. J Bacteriol. 2006;188(5):1959–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Davies TA, Shang W, Bush K. Activities of ceftobiprole and other beta-lactams against Streptococcus pneumoniae clinical isolates from the United States with defined substitutions in penicillin-binding proteins PBP 1a, PBP 2b, and PBP 2x. Antimicrob Agents Chemother. 2006;50(7):2530–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. McGee L, Biek D, Ge Y, Klugman M, du Plessis M, Smith AM, et al. In vitro evaluation of the antimicrobial activity of ceftaroline against cephalosporin-resistant isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother. 2009;53(2):552–6. doi:10.1128/AAC.01324-08.

    Article  CAS  PubMed  Google Scholar 

  222. Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2011;52(9):1156–63. doi:10.1093/cid/cir147.

    Article  CAS  PubMed  Google Scholar 

  223. Zervosen A, Zapun A, Frere JM. Inhibition of Streptococcus pneumoniae penicillin-binding protein 2x and Actinomadura R39 DD-peptidase activities by ceftaroline. Antimicrob Agents Chemother. 2013;57(1):661–3. doi:10.1128/AAC.01593-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Macheboeuf P, Fischer DS, Brown Jr T, Zervosen A, Luxen A, Joris B, et al. Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins. Nat Chem Biol. 2007;3(9):565–9. doi:10.1038/nchembio.2007.21.

    Article  CAS  PubMed  Google Scholar 

  225. Hermida M, Roy C, Baro MT, Reig R, Tirado M. Characterization of penicillinase-producing strains of Neisseria gonorrhoeae. Eur J Clin Microbiol Infect Dis. 1993;12(1):45–8.

    Article  CAS  PubMed  Google Scholar 

  226. Backman A, Orvelid P, Vazquez JA, Skold O, Olcen P. Complete sequence of a beta-lactamase-encoding plasmid in Neisseria meningitidis. Antimicrob Agents Chemother. 2000;44(1):210–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Dougherty TJ, Koller AE, Tomasz A. Penicillin-binding proteins of penicillin-susceptible and intrinsically resistant Neisseria gonorrhoeae. Antimicrob Agents Chemother. 1980;18(5):730–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Mendelman PM, Campos J, Chaffin DO, Serfass DA, Smith AL, Saez-Nieto JA. Relative penicillin G resistance in Neisseria meningitidis and reduced affinity of penicillin-binding protein 3. Antimicrob Agents Chemother. 1988;32(5):706–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Spratt BG. Hybrid penicillin-binding proteins in penicillin-resistant strains of Neisseria gonorrhoeae. Nature. 1988;332(6160):173–6.

    Article  CAS  PubMed  Google Scholar 

  230. Spratt BG, Zhang QY, Jones DM, Hutchison A, Brannigan JA, Dowson CG. Recruitment of a penicillin-binding protein gene from Neisseria flavescens during the emergence of penicillin resistance in Neisseria meningitidis. Proc Natl Acad Sci U S A. 1989;86(22):8988–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Taha MK, Vazquez JA, Hong E, Bennett DE, Bertrand S, Bukovski S, et al. Target gene sequencing to characterize the penicillin G susceptibility of Neisseria meningitidis. Antimicrob Agents Chemother. 2007;51(8):2784–92. doi:10.1128/AAC.00412-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Thulin S, Olcen P, Fredlund H, Unemo M. Total variation in the penA gene of Neisseria meningitidis: correlation between susceptibility to beta-lactam antibiotics and penA gene heterogeneity. Antimicrob Agents Chemother. 2006;50(10):3317–24. doi:10.1128/AAC.00353-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Allen VG, Farrell DJ, Rebbapragada A, Tan J, Tijet N, Perusini SJ, et al. Molecular analysis of antimicrobial resistance mechanisms in Neisseria gonorrhoeae isolates from Ontario. Canada Antimicrob Agents Chemother. 2011;55(2):703–12. doi:10.1128/AAC.00788-10.

    Article  CAS  PubMed  Google Scholar 

  234. Camara J, Serra J, Ayats J, Bastida T, Carnicer-Pont D, Andreu A, et al. Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain. J Antimicrob Chemother. 2012;67(8):1858–60. doi:10.1093/jac/dks162.

    Article  CAS  PubMed  Google Scholar 

  235. Ito M, Deguchi T, Mizutani KS, Yasuda M, Yokoi S, Ito S, et al. Emergence and spread of Neisseria gonorrhoeae clinical isolates harboring mosaic-like structure of penicillin-binding protein 2 in Central Japan. Antimicrob Agents Chemother. 2005;49(1):137–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Liao M, Gu WM, Yang Y, Dillon JA. Analysis of mutations in multiple loci of Neisseria gonorrhoeae isolates reveals effects of PIB, PBP2 and MtrR on reduced susceptibility to ceftriaxone. J Antimicrob Chemother. 2011;66(5):1016–23. doi:10.1093/jac/dkr021.

    Article  CAS  PubMed  Google Scholar 

  237. Lindberg R, Fredlund H, Nicholas R, Unemo M. Neisseria gonorrhoeae isolates with reduced susceptibility to cefixime and ceftriaxone: association with genetic polymorphisms in penA, mtrR, porB1b, and ponA. Antimicrob Agents Chemother. 2007;51(6):2117–22. doi:10.1128/AAC.01604-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Pandori M, Barry PM, Wu A, Ren A, Whittington WL, Liska S, et al. Mosaic penicillin-binding protein 2 in Neisseria gonorrhoeae isolates collected in 2008 in San Francisco, California. Antimicrob Agents Chemother. 2009;53(9):4032–4. doi:10.1128/AAC.00406-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Takahata S, Senju N, Osaki Y, Yoshida T, Ida T. Amino acid substitutions in mosaic penicillin-binding protein 2 associated with reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2006;50(11):3638–45. doi:10.1128/AAC.00626-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Whiley DM, Limnios EA, Ray S, Sloots TP, Tapsall JW. Diversity of penA alterations and subtypes in Neisseria gonorrhoeae strains from Sydney, Australia, that are less susceptible to ceftriaxone. Antimicrob Agents Chemother. 2007;51(9):3111–6. doi:10.1128/AAC.00306-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Heymans R, Bruisten SM, Golparian D, Unemo M, de Vries HJ, van Dam AP. Clonally related Neisseria gonorrhoeae isolates with decreased susceptibility to the extended-spectrum cephalosporin cefotaxime in Amsterdam, the Netherlands. Antimicrob Agents Chemother. 2012;56(3):1516–22. doi:10.1128/AAC.05481-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Fussenegger M, Rudel T, Barten R, Ryll R, Meyer TF. Transformation competence and type-4 pilus biogenesis in Neisseria gonorrhoeae—a review. Gene. 1997;192(1):125–34.

    Article  CAS  PubMed  Google Scholar 

  243. Ohnishi M, Watanabe Y, Ono E, Takahashi C, Oya H, Kuroki T, et al. Spread of a chromosomal cefixime-resistant penA gene among different Neisseria gonorrhoeae lineages. Antimicrob Agents Chemother. 2010;54(3):1060–7. doi:10.1128/AAC.01010-09.

    Article  CAS  PubMed  Google Scholar 

  244. Ameyama S, Onodera S, Takahata M, Minami S, Maki N, Endo K, et al. Mosaic-like structure of penicillin-binding protein 2 Gene (penA) in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime. Antimicrob Agents Chemother. 2002;46(12):3744–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Bowler LD, Zhang QY, Riou JY, Spratt BG. Interspecies recombination between the penA genes of Neisseria meningitidis and commensal Neisseria species during the emergence of penicillin resistance in N. meningitidis: natural events and laboratory simulation. J Bacteriol. 1994;176(2):333–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Spratt BG, Bowler LD, Zhang QY, Zhou J, Smith JM. Role of interspecies transfer of chromosomal genes in the evolution of penicillin resistance in pathogenic and commensal Neisseria species. J Mol Evol. 1992;34(2):115–25.

    Article  CAS  PubMed  Google Scholar 

  247. Lee SG, Lee H, Jeong SH, Yong D, Chung GT, Lee YS, et al. Various penA mutations together with mtrR, porB and ponA mutations in Neisseria gonorrhoeae isolates with reduced susceptibility to cefixime or ceftriaxone. J Antimicrob Chemother. 2010;65(4):669–75. doi:10.1093/jac/dkp505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Brannigan JA, Tirodimos IA, Zhang QY, Dowson CG, Spratt BG. Insertion of an extra amino acid is the main cause of the low affinity of penicillin-binding protein 2 in penicillin-resistant strains of Neisseria gonorrhoeae. Mol Microbiol. 1990;4(6):913–9.

    Article  CAS  PubMed  Google Scholar 

  249. Powell AJ, Tomberg J, Deacon AM, Nicholas RA, Davies C. Crystal structures of penicillin-binding protein 2 from penicillin-susceptible and -resistant strains of Neisseria gonorrhoeae reveal an unexpectedly subtle mechanism for antibiotic resistance. J Biol Chem. 2009;284(2):1202–12. doi:10.1074/jbc.M805761200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Tomberg J, Temple B, Fedarovich A, Davies C, Nicholas RA. A highly conserved interaction involving the middle residue of the SXN active-site motif is crucial for function of class B penicillin-binding proteins: mutational and computational analysis of PBP 2 from N. gonorrhoeae. Biochemistry. 2012;51(13):2775–84. doi:10.1021/bi2017987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Osaka K, Takakura T, Narukawa K, Takahata M, Endo K, Kiyota H, et al. Analysis of amino acid sequences of penicillin-binding protein 2 in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime and ceftriaxone. J Infect Chemother. 2008;14(3):195–203. doi:10.1007/s10156-008-0610-7.

    Article  CAS  PubMed  Google Scholar 

  252. Tomberg J, Unemo M, Davies C, Nicholas RA. Molecular and structural analysis of mosaic variants of penicillin-binding protein 2 conferring decreased susceptibility to expanded-spectrum cephalosporins in Neisseria gonorrhoeae: role of epistatic mutations. Biochemistry. 2010;49(37):8062–70. doi:10.1021/bi101167x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother. 2012;56(3):1273–80. doi:10.1128/AAC.05760-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Whiley DM, Goire N, Lambert SB, Ray S, Limnios EA, Nissen MD, et al. Reduced susceptibility to ceftriaxone in Neisseria gonorrhoeae is associated with mutations G542S, P551S and P551L in the gonococcal penicillin-binding protein 2. J Antimicrob Chemother. 2010;65(8):1615–8. doi:10.1093/jac/dkq187.

    Article  CAS  PubMed  Google Scholar 

  255. Lujan R, Zhang QY, Saez Nieto JA, Jones DM, Spratt BG. Penicillin-resistant isolates of Neisseria lactamica produce altered forms of penicillin-binding protein 2 that arose by interspecies horizontal gene transfer. Antimicrob Agents Chemother. 1991;35(2):300–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Saez-Nieto JA, Lujan R, Martinez-Suarez JV, Berron S, Vazquez JA, Vinas M, et al. Neisseria lactamica and Neisseria polysaccharea as possible sources of meningococcal beta-lactam resistance by genetic transformation. Antimicrob Agents Chemother. 1990;34(11):2269–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Antignac A, Boneca IG, Rousselle JC, Namane A, Carlier JP, Vazquez JA, et al. Correlation between alterations of the penicillin-binding protein 2 and modifications of the peptidoglycan structure in Neisseria meningitidis with reduced susceptibility to penicillin G. J Biol Chem. 2003;278(34):31529–35.

    Article  CAS  PubMed  Google Scholar 

  258. Ropp PA, Hu M, Olesky M, Nicholas RA. Mutations in ponA, the gene encoding penicillin-binding protein 1, and a novel locus, penC, are required for high-level chromosomally mediated penicillin resistance in Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2002;46(3):769–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Hagman KE, Pan W, Spratt BG, Balthazar JT, Judd RC, Shafer WM. Resistance of Neisseria gonorrhoeae to antimicrobial hydrophobic agents is modulated by the mtrRCDE efflux system. Microbiology. 1995;141(Pt 3):611–22.

    Article  CAS  PubMed  Google Scholar 

  260. Gill MJ, Simjee S, Al-Hattawi K, Robertson BD, Easmon CS, Ison CA. Gonococcal resistance to beta-lactams and tetracycline involves mutation in loop 3 of the porin encoded at the penB locus. Antimicrob Agents Chemother. 1998;42(11):2799–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Markowitz SM. Isolation of an ampicillin-resistant, non-beta-lactamase-producing strain of Haemophilus influenzae. Antimicrob Agents Chemother. 1980;17(1):80–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Hasegawa K, Chiba N, Kobayashi R, Murayama SY, Iwata S, Sunakawa K, et al. Rapidly increasing prevalence of beta-lactamase-nonproducing, ampicillin-resistant Haemophilus influenzae type b in patients with meningitis. Antimicrob Agents Chemother. 2004;48(5):1509–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Mendelman PM, Chaffin DO, Stull TL, Rubens CE, Mack KD, Smith AL. Characterization of non-beta-lactamase-mediated ampicillin resistance in Haemophilus influenzae. Antimicrob Agents Chemother. 1984;26(2):235–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Mendelman PM, Chaffin DO, Krilov LR, Kalaitzoglou G, Serfass DA, Onay O, et al. Cefuroxime treatment failure of nontypable Haemophilus influenzae meningitis associated with alteration of penicillin-binding proteins. J Infect Dis. 1990;162(5):1118–23.

    Article  CAS  PubMed  Google Scholar 

  265. Mendelman PM, Chaffin DO, Musser JM, De Groot R, Serfass DA, Selander RK. Genetic and phenotypic diversity among ampicillin-resistant, non-beta-lactamase-producing, nontypeable Haemophilus influenzae isolates. Infect Immun. 1987;55(11):2585–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  266. Clairoux N, Picard M, Brochu A, Rousseau N, Gourde P, Beauchamp D, et al. Molecular basis of the non-beta-lactamase-mediated resistance to beta-lactam antibiotics in strains of Haemophilus influenzae isolated in Canada. Antimicrob Agents Chemother. 1992;36(7):1504–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Malouin F, Schryvers AB, Bryan LE. Cloning and expression of genes responsible for altered penicillin-binding proteins 3a and 3b in Haemophilus influenzae. Antimicrob Agents Chemother. 1987;31(2):286–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Parr Jr TR, Bryan LE. Mechanism of resistance of an ampicillin-resistant, beta-lactamase-negative clinical isolate of Haemophilus influenzae type b to beta-lactam antibiotics. Antimicrob Agents Chemother. 1984;25(6):747–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Ubukata K, Shibasaki Y, Yamamoto K, Chiba N, Hasegawa K, Takeuchi Y, et al. Association of amino acid substitutions in penicillin-binding protein 3 with beta-lactam resistance in beta-lactamase-negative ampicillin-resistant Haemophilus influenzae. Antimicrob Agents Chemother. 2001;45(6):1693–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Kaczmarek FS, Gootz TD, Dib-Hajj F, Shang W, Hallowell S, Cronan M. Genetic and molecular characterization of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae with unusually high resistance to ampicillin. Antimicrob Agents Chemother. 2004;48(5):1630–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Barbosa AR, Giufre M, Cerquetti M, Bajanca-Lavado MP. Polymorphism in ftsI gene and {beta}-lactam susceptibility in Portuguese Haemophilus influenzae strains: clonal dissemination of beta-lactamase-positive isolates with decreased susceptibility to amoxicillin/clavulanic acid. J Antimicrob Chemother. 2011;66(4):788–96. doi:10.1093/jac/dkq533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Dabernat H, Delmas C, Seguy M, Pelissier R, Faucon G, Bennamani S, et al. Diversity of beta-lactam resistance-conferring amino acid substitutions in penicillin-binding protein 3 of Haemophilus influenzae. Antimicrob Agents Chemother. 2002;46(7):2208–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Garcia-Cobos S, Campos J, Lazaro E, Roman F, Cercenado E, Garcia-Rey C, et al. Ampicillin-resistant non-beta-lactamase-producing Haemophilus influenzae in Spain: recent emergence of clonal isolates with increased resistance to cefotaxime and cefixime. Antimicrob Agents Chemother. 2007;51(7):2564–73. doi:10.1128/AAC.00354-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Sanbongi Y, Suzuki T, Osaki Y, Senju N, Ida T, Ubukata K. Molecular evolution of beta-lactam-resistant Haemophilus influenzae: 9-year surveillance of penicillin-binding protein 3 mutations in isolates from Japan. Antimicrob Agents Chemother. 2006;50(7):2487–92. doi:10.1128/AAC.01316-05.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Shuel ML, Tsang RS. Canadian beta-lactamase-negative Haemophilus influenzae isolates showing decreased susceptibility toward ampicillin have significant penicillin binding protein 3 mutations. Diagn Microbiol Infect Dis. 2009;63(4):379–83. doi:10.1016/j.diagmicrobio.2008.12.015.

    Article  CAS  PubMed  Google Scholar 

  276. Takahata S, Ida T, Senju N, Sanbongi Y, Miyata A, Maebashi K, et al. Horizontal gene transfer of ftsI, encoding penicillin-binding protein 3, in Haemophilus influenzae. Antimicrob Agents Chemother. 2007;51(5):1589–95. doi:10.1128/AAC.01545-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Witherden EA, Bajanca-Lavado MP, Tristram SG, Nunes A. Role of inter-species recombination of the ftsI gene in the dissemination of altered penicillin-binding-protein-3-mediated resistance in Haemophilus influenzae and Haemophilus haemolyticus. J Antimicrob Chemother. 2014;69(6):1501–9. doi:10.1093/jac/dku022.

    Article  CAS  PubMed  Google Scholar 

  278. Osaki Y, Sanbongi Y, Ishikawa M, Kataoka H, Suzuki T, Maeda K, et al. Genetic approach to study the relationship between penicillin-binding protein 3 mutations and Haemophilus influenzae beta-lactam resistance by using site-directed mutagenesis and gene recombinants. Antimicrob Agents Chemother. 2005;49(7):2834–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Kishii K, Chiba N, Morozumi M, Hamano-Hasegawa K, Kurokawa I, Masaki J, et al. Diverse mutations in the ftsI gene in ampicillin-resistant Haemophilus influenzae isolates from pediatric patients with acute otitis media. J Infect Chemother. 2010;16(2):87–93. doi:10.1007/s10156-009-0011-6.

    Article  CAS  PubMed  Google Scholar 

  280. Cerquetti M, Giufre M, Cardines R, Mastrantonio P. First characterization of heterogeneous resistance to imipenem in invasive nontypeable Haemophilus influenzae isolates. Antimicrob Agents Chemother. 2007;51(9):3155–61. doi:10.1128/AAC.00335-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Okabe T, Yamazaki Y, Shiotani M, Suzuki T, Shiohara M, Kasuga E, et al. An amino acid substitution in PBP-3 in Haemophilus influenzae associate with the invasion to bronchial epithelial cells. Microbiol Res. 2010;165(1):11–20. doi:10.1016/j.micres.2008.03.003.

    Article  CAS  PubMed  Google Scholar 

  282. Bozdogan B, Tristram S, Appelbaum PC. Combination of altered PBPs and expression of cloned extended-spectrum beta-lactamases confers cefotaxime resistance in Haemophilus influenzae. J Antimicrob Chemother. 2006;57(4):747–9. doi:10.1093/jac/dkl039.

    Article  CAS  PubMed  Google Scholar 

  283. Matic V, Bozdogan B, Jacobs MR, Ubukata K, Appelbaum PC. Contribution of beta-lactamase and PBP amino acid substitutions to amoxicillin/clavulanate resistance in beta-lactamase-positive, amoxicillin/clavulanate-resistant Haemophilus influenzae. J Antimicrob Chemother. 2003;52(6):1018–21.

    Article  CAS  PubMed  Google Scholar 

  284. San Millan A, Giufre M, Escudero JA, Hidalgo L, Gutierrez B, Cerquetti M, et al. Contribution of ROB-1 and PBP3 mutations to the resistance phenotype of a beta-lactamase-positive amoxicillin/clavulanic acid-resistant Haemophilus influenzae carrying plasmid pB1000 in Italy. J Antimicrob Chemother. 2011;66(1):96–9. doi:10.1093/jac/dkq392.

    Article  CAS  PubMed  Google Scholar 

  285. Tristram SG, Littlejohn R, Bradbury RS. blaROB-1 presence on pB1000 in Haemophilus influenzae is widespread, and variable cefaclor resistance is associated with altered penicillin-binding proteins. Antimicrob Agents Chemother. 2010;54(11):4945–7. doi:10.1128/AAC.00263-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Garcia-Cobos S, Arroyo M, Campos J, Perez-Vazquez M, Aracil B, Cercenado E, et al. Novel mechanisms of resistance to beta-lactam antibiotics in Haemophilus parainfluenzae: beta-lactamase-negative ampicillin resistance and inhibitor-resistant TEM beta-lactamases. J Antimicrob Chemother. 2013;68(5):1054–9. doi:10.1093/jac/dks525.

    Article  CAS  PubMed  Google Scholar 

  287. Krishnamurthy P, Parlow MH, Schneider J, Burroughs S, Wickland C, Vakil NB, et al. Identification of a novel penicillin-binding protein from Helicobacter pylori. J Bacteriol. 1999;181(16):5107–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  288. Dore MP, Osato MS, Realdi G, Mura I, Graham DY, Sepulveda AR. Amoxycillin tolerance in Helicobacter pylori. J Antimicrob Chemother. 1999;43(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  289. Dore MP, Graham DY, Sepulveda AR. Different penicillin-binding protein profiles in amoxicillin-resistant Helicobacter pylori. Helicobacter. 1999;4(3):154–61.

    Article  CAS  PubMed  Google Scholar 

  290. Gerrits MM, Schuijffel D, van Zwet AA, Kuipers EJ, Vandenbroucke-Grauls CM, Kusters JG. Alterations in penicillin-binding protein 1A confer resistance to beta-lactam antibiotics in Helicobacter pylori. Antimicrob Agents Chemother. 2002;46(7):2229–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Han SR, Bhakdi S, Maeurer MJ, Schneider T, Gehring S. Stable and unstable amoxicillin resistance in Helicobacter pylori: should antibiotic resistance testing be performed prior to eradication therapy? J Clin Microbiol. 1999;37(8):2740–1.

    CAS  PubMed  PubMed Central  Google Scholar 

  292. Okamoto T, Yoshiyama H, Nakazawa T, Park ID, Chang MW, Yanai H, et al. A change in PBP1 is involved in amoxicillin resistance of clinical isolates of Helicobacter pylori. J Antimicrob Chemother. 2002;50(6):849–56.

    Article  CAS  PubMed  Google Scholar 

  293. van Zwet AA, Vandenbroucke-Grauls CM, Thijs JC, van der Wouden EJ, Gerrits MM, Kusters JG, et al. Stable amoxicillin resistance in Helicobacter pylori. Lancet. 1998;352(9140):1595.

    Article  PubMed  Google Scholar 

  294. Kwon DH, Dore MP, Kim JJ, Kato M, Lee M, Wu JY, et al. High-level beta-lactam resistance associated with acquired multidrug resistance in Helicobacter pylori. Antimicrob Agents Chemother. 2003;47(7):2169–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Matteo MJ, Granados G, Olmos M, Wonaga A, Catalano M. Helicobacter pylori amoxicillin heteroresistance due to point mutations in PBP-1A in isogenic isolates. J Antimicrob Chemother. 2008;61(3):474–7. doi:10.1093/jac/dkm504.

    Article  CAS  PubMed  Google Scholar 

  296. Kim BJ, Kim JG. Substitutions in penicillin-binding protein 1 in amoxicillin-resistant Helicobacter pylori strains isolated from Korean patients. Gut Liver. 2013;7(6):655–60. doi:10.5009/gnl.2013.7.6.655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Qureshi NN, Morikis D, Schiller NL. Contribution of specific amino acid changes in penicillin binding protein 1 to amoxicillin resistance in clinical Helicobacter pylori isolates. Antimicrob Agents Chemother. 2011;55(1):101–9. doi:10.1128/AAC.00545-10.

    Article  CAS  PubMed  Google Scholar 

  298. Co EM, Schiller NL. Resistance mechanisms in an in vitro-selected amoxicillin-resistant strain of Helicobacter pylori. Antimicrob Agents Chemother. 2006;50(12):4174–6. doi:10.1128/AAC.00759-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. DeLoney CR, Schiller NL. Characterization of an In vitro-selected amoxicillin-resistant strain of Helicobacter pylori. Antimicrob Agents Chemother. 2000;44(12):3368–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Paul R, Postius S, Melchers K, Schafer KP. Mutations of the Helicobacter pylori genes rdxA and pbp1 cause resistance against metronidazole and amoxicillin. Antimicrob Agents Chemother. 2001;45(3):962–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Rimbara E, Noguchi N, Kawai T, Sasatsu M. Mutations in penicillin-binding proteins 1, 2 and 3 are responsible for amoxicillin resistance in Helicobacter pylori. J Antimicrob Chemother. 2008;61(5):995–8. doi:10.1093/jac/dkn051.

    Article  CAS  PubMed  Google Scholar 

  302. Spratt BG. Escherichia coli resistance to beta-lactam antibiotics through a decrease in the affinity of a target for lethality. Nature. 1978;274(5672):713–5.

    Article  CAS  PubMed  Google Scholar 

  303. Hedge PJ, Spratt BG. Amino acid substitutions that reduce the affinity of penicillin-binding protein 3 of Escherichia coli for cephalexin. Eur J Biochem. 1985;151(1):111–21.

    Article  CAS  PubMed  Google Scholar 

  304. Hedge PJ, Spratt BG. Resistance to beta-lactam antibiotics by re-modelling the active site of an E. coli penicillin-binding protein. Nature. 1985;318(6045):478–80.

    Article  CAS  PubMed  Google Scholar 

  305. Neuwirth C, Siebor E, Duez JM, Pechinot A, Kazmierczak A. Imipenem resistance in clinical isolates of Proteus mirabilis associated with alterations in penicillin-binding proteins. J Antimicrob Chemother. 1995;36(2):335–42.

    Article  CAS  PubMed  Google Scholar 

  306. Bellido F, Veuthey C, Blaser J, Bauernfeind A, Pechere JC. Novel resistance to imipenem associated with an altered PBP-4 in a Pseudomonas aeruginosa clinical isolate. J Antimicrob Chemother. 1990;25(1):57–68.

    Article  CAS  PubMed  Google Scholar 

  307. Gotoh N, Nunomura K, Nishino T. Resistance of Pseudomonas aeruginosa to cefsulodin: modification of penicillin-binding protein 3 and mapping of its chromosomal gene. J Antimicrob Chemother. 1990;25(4):513–23.

    Article  CAS  PubMed  Google Scholar 

  308. Bellido F, Vladoianu IR, Auckenthaler R, Suter S, Wacker P, Then RL, et al. Permeability and penicillin-binding protein alterations in Salmonella muenchen: stepwise resistance acquired during beta-lactam therapy. Antimicrob Agents Chemother. 1989;33(7):1113–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  309. Obara M, Nakae T. Mechanisms of resistance to beta-lactam antibiotics in Acinetobacter calcoaceticus. J Antimicrob Chemother. 1991;28(6):791–800.

    Article  CAS  PubMed  Google Scholar 

  310. Gehrlein M, Leying H, Cullmann W, Wendt S, Opferkuch W. Imipenem resistance in Acinetobacter baumanii is due to altered penicillin-binding proteins. Chemotherapy. 1991;37(6):405–12.

    Article  CAS  PubMed  Google Scholar 

  311. Vashist J, Tiwari V, Das R, Kapil A, Rajeswari MR. Analysis of penicillin-binding proteins (PBPs) in carbapenem resistant Acinetobacter baumannii. Indian J Med Res. 2011;133:332–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  312. Cayo R, Rodriguez MC, Espinal P, Fernandez-Cuenca F, Ocampo-Sosa AA, Pascual A, et al. Analysis of genes encoding penicillin-binding proteins in clinical isolates of Acinetobacter baumannii. Antimicrob Agents Chemother. 2011;55(12):5907–13. doi:10.1128/AAC.00459-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  313. Gutkind GO, Ogueta SB, de Urtiaga AC, Mollerach ME, de Torres RA. Participation of PBP 3 in the acquisition of dicloxacillin resistance in Listeria monocytogenes. J Antimicrob Chemother. 1990;25(5):751–8.

    Article  CAS  PubMed  Google Scholar 

  314. Pierre J, Boisivon A, Gutmann L. Alteration of PBP 3 entails resistance to imipenem in Listeria monocytogenes. Antimicrob Agents Chemother. 1990;34(9):1695–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  315. Wexler HM, Halebian S. Alterations to the penicillin-binding proteins in the Bacteroides fragilis group: a mechanism for non-beta-lactamase mediated cefoxitin resistance. J Antimicrob Chemother. 1990;26(1):7–20.

    Article  CAS  PubMed  Google Scholar 

  316. Nordmann P, Nicolas MH, Gutmann L. Penicillin-binding proteins of Rhodococcus equi: potential role in resistance to imipenem. Antimicrob Agents Chemother. 1993;37(7):1406–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  317. Paradkar AS, Aidoo KA, Wong A, Jensen SE. Molecular analysis of a beta-lactam resistance gene encoded within the cephamycin gene cluster of Streptomyces clavuligerus. J Bacteriol. 1996;178(21):6266–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  318. Coque JJ, Liras P, Martin JF. Genes for a beta-lactamase, a penicillin-binding protein and a transmembrane protein are clustered with the cephamycin biosynthetic genes in Nocardia lactamdurans. Embo J. 1993;12(2):631–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  319. Zervosen A, Lu WP, Chen Z, White RE, Demuth Jr TP, Frere JM. Interactions between penicillin-binding proteins (PBPs) and two novel classes of PBP inhibitors, arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones. Antimicrob Agents Chemother. 2004;48(3):961–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Structural Biology, CNRS, CEA, Université Grenoble Alpes, Grenoble, France

    André Zapun, Pauline Macheboeuf & Thierry Vernet

Authors
  1. André Zapun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pauline Macheboeuf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thierry Vernet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to André Zapun .

Editor information

Editors and Affiliations

  1. Treiber Therapeutics, Cambridge, Massachusetts, USA

    Douglas L. Mayers

  2. Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA

    Jack D. Sobel

  3. Centre de recherche en Infectiologie, University of Laval, Quebec City, Canada

    Marc Ouellette

  4. Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Keith S. Kaye

  5. Infection Control and Prevention Unit of Infectious Diseases, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Dror Marchaim

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Zapun, A., Macheboeuf, P., Vernet, T. (2017). Penicillin-Binding Proteins and β-Lactam Resistance. In: Mayers, D., Sobel, J., Ouellette, M., Kaye, K., Marchaim, D. (eds) Antimicrobial Drug Resistance. Springer, Cham. https://doi.org/10.1007/978-3-319-46718-4_13

Download citation

Publish with us

Policies and ethics

Search

Navigation