Molecular Adaptations in Resistance to Penicillins and Other β-Lactam Antibiotics

  • J. Coyette
  • M. Nguyen-Distèche
  • J. Lamotte-Brasseur
  • B. Joris
  • E. Fonzé
  • J.-M. Frère
Part of the Advances in Comparative and Environmental Physiology book series (COMPARATIVE, volume 20)


The chance discovery by Fleming in 1928 of a metabolite produced by Penicillium notatum which exhibited bacteriolytic properties was followed by the heroic efforts of the Oxford group of Chain and Florey to isolate and identify the active molecule. This led to the introduction of benzylpenicillin in clinical trials about 50 years ago, probably one of the major breakthroughs in modern chemotherapy. Although some pathogenic bacteria were rapidly recognized as resistant to the new wonder drug, it was believed that a nearly ideal solution had been found to the problem of bacteria-mediated infectious diseases. Indeed, penicillin was extremely efficient and nearly completely innocuous to eukaryotic cells, which allowed the utilization of relatively high doses with little or no unwanted secondary effects. However, in the early 1950s, resistant strains started to appear in generally sensitive species such as Staphylococcus aureus and this phenomenon initiated a constant struggle between chemists, biochemists and microbiologists, on the one side, and bacteria, on the other. The former continuously isolated new molecules from natural sources and synthesized additional compounds, while the latter kept devising new strategies to escape the lethal action of an ever expanding arsenal of drugs which exhibited one common chemical characteristic: the presence of the four-membered β-lactam ring shown in Fig. 1 (together with some members of the β-lactam family).


Antimicrob Agent Neisseria Gonorrhoeae Molecular Adaptation Mosaic Gene Peptidoglycan Precursor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abraham EP, Chain E (1940) An enzyme from bacteria able to destroy penicillin. Nature 146: 837Google Scholar
  2. Al Obeid S, Gutmann L, Williamson R (1990) Correlation of penicillin-induced lysis of Enterococcusfaecium with saturation of essential penicillin-binding proteins and release of lipoteichoic acid. Antimicrob Agents Chemother 34: 1901–1907Google Scholar
  3. Ambler RP, Coulson AF, Frère JM, Ghuysen JM, Jaurin B, Joris B, Levesque R, Tiraby G, Waley SG (1991) A standard numbering scheme for the class A beta-lactamases. Biochem J 276: 269–272PubMedGoogle Scholar
  4. Barthélémy M, Peduzzi J, Yaghlane HB, Labia R (1988) Single amino acid substituion between SHV-1 ß-lactamase and cefotaxime-hydrolysing SHV-2 enzyme. FEBS Lett 231: 217–220PubMedGoogle Scholar
  5. Begg KJ, Takasuga A, Edwards DH, Dewar SJ, Spratt BG, Adachi H, Ohta T, Matsuzawa H, Donachie WD (1990) The balance between different peptidoglycan precursors determines whether Escherichia coli will elongate or divide. J Bacteriol 172: 6697–6703PubMedGoogle Scholar
  6. Boyce JM, Opal SM, Potter-Bynoe G, La Forge RG, Zorvos MJ, Furtado G, Victor G, Medeiros AA (1992) Emergence and transmission of ampicillin-resistant enterococci. Antimicrob Agents Chemother 36: 1032–1039PubMedGoogle Scholar
  7. Berger-Bächi B, Strassle A, Gustason JE, Kayser FH (1992) Mapping and characterization of multiple chromosomal factors involved in methicillin-resistance in Staphylococcus aureus. Antimicrob Agents Chemother 36: 1367–1373PubMedGoogle Scholar
  8. Boyce JM, Opal SM, Potter-Bynoe G, La Forge RG, Zorvos MJ, Furtado G, Victor G, Medeiros AA (1992) Emergence and transmission of ampicillin-resistant enterococci. Antimicrob Agents Chemother 36: 1032–1039PubMedGoogle Scholar
  9. Brannigan JA, Tirodimos IA, Zhang QY, Dowson CG, Spratt BG (1990) 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 4: 913–919PubMedGoogle Scholar
  10. Brenner DG, Knowles JR (1984) Penicillanic acid sulfone: nature of irreversible inactivation of RTEM ß-lactamase from E. coli Biochemistry 23: 5833–5839Google Scholar
  11. Bugg TDH, Dutka-Malen S, Arthur M, Courvalin P, Walsh CT (1991a) Identification of vancomycin resistance protein VanA as D-alanine ligase of altered substrate specificity. Biochemistry 30: 2017–2021PubMedGoogle Scholar
  12. Bugg TDH, Wright GD, Dutka-Malen S, Arthur M, Courvalin P, Walsh CT (1991b) Molecular basis for vancomycin resistance in Enterococcus faecium BM4147: biosyntheis of depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA. Biochemistry 30: 10408–10415PubMedGoogle Scholar
  13. Bush K (1989a) Characterization of ß-lactamases. Antimicrob Agents Chemother 33: 259–263PubMedGoogle Scholar
  14. Bush K (1989b) Excitement in the beta-lactamase area. J Antimicrob 24: 831–836Google Scholar
  15. Courvalin P (1990) Resistance of enterococci to glycopeptides. Antimicorb Agents Chemother 34: 2291–2296Google Scholar
  16. Couture F, Lachapelle J, Levesque RC (1992) Phylogeny of LCR-1 and OXA-5 with class A and class D ß-lactamases. Mol Microbiol 6: 1693–1705PubMedGoogle Scholar
  17. Cowan SW, Schirmer T, Rummel G, Ghosh R, Pauptit RA, Jansonius JN, Rosenbusch JP (1992) Crystal structures explain functional properties of two E. coli porins. Nature 358: 727–733PubMedGoogle Scholar
  18. Degelaen J, Feeney J, Roberts GC, Burgen AS, Frère JM, Ghuysen JM (1979) NMR evidence for the structure of the complex between penicillin and the DD-carboxypeptidase of Streptomyces R61. FEBS Lett 98: 53–56PubMedGoogle Scholar
  19. de Jonge BL, Chang YS, Gage D, Tomasz A (1992) Peptidoglycan comparison of a highly methicillin-resistant Staphylococcus aureus strain. The role of penicillin-binding protein 2A. J Biol Chem 267: 11248–11254PubMedGoogle Scholar
  20. Delaire M, Labia R, Samama JP, Masson JM (1992) Site-directed mutagenesis at the active site of Escherichia coli TEM-1 ß-lactamase. Suicide inhibitor-resistant mutants reveal the role of arginine 244 and methionine 69 in catalysis. J Biol Chem 267: 20600–20606PubMedGoogle Scholar
  21. de Lencastre H, Sa Figueiredo AM, Urban C, Rahal J, Tomasz A (1991) Multiple mechanism of methicillin resistance and improved methods for detection in clinical isolates of Staphylococcus aureus. Antimicrob Agents Chemother 35: 632–639PubMedGoogle Scholar
  22. del Mar Lleo M, Canepari P, Cornaglia G, Fontana R, Satta G (1987) Bacteriostatic and bactericidal activities of ß-lactams against Streptococcus (Enterococcus) faecium are associated with saturation of different penicillin-binding proteins. Antimicrob Agents Chemother 31: 1618–1626PubMedGoogle Scholar
  23. Dowson CG, Hutchison A, Woodford N, Johnson AP, George RC, Spratt BG (1990) Penicillin-resistant viridans streptococci have obtained altered penicillin-binding protein genes from penicillin-resistant strains of Streptococcus pneumoniae. Proc Natl Acad Sci USA 87: 5858–5862PubMedGoogle Scholar
  24. Dowson CG, Hutchison A, Brannigan JA, George RC, Hansman D, Linares J, Tomasz A, Smith JM, Spratt BG (1989) Horizontal transfer of penicillin-binding protein genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Proc Natl Acad Sci USA 86: 8842–8846PubMedGoogle Scholar
  25. Dowson CG, Hutchison A, Woodford N, Johnson AP, George RC, Spratt BG (1990) Penicillin-resistant viridans streptococci have obtained altered penicillin-binding protein genes from penicillin-resistant strains of Streptococcus pneumoniae. Proc Natl Acad Sci USA 87: 5858–5862PubMedGoogle Scholar
  26. El Kharroubi A, Jacques P, Piras G, Van Beeumen J, Coyette J, Ghuysen JM (1991) The Enterococcus hirae R40 penicillin-binding protein 5 and the methicillin-resistant Staphylococcus aureus penicillin-binding protein 2’ are similar. Biochem J 280: 463–469PubMedGoogle Scholar
  27. Faruki H, Sparling RF (1986) Genetics of resistance in non-ß-lactamase producing gonococcus with relatively high-level penicillin resistance. Antimicrob Agents Chemother 30: 856–860PubMedGoogle Scholar
  28. Fisher J, Charnas RL, Knowles JR (1978) Kinetic studies on the inactivation of Escherichia coli RTEM beta-lactamase by clavulanic acid. Biochemistry 17: 2180–2184PubMedGoogle Scholar
  29. Fontana R, Cerini R, Longoni P, Grossato A, Canepari P (1983) Identification of a streptococcal penicillin-binding protein that reacts very slowly with penicillin. J Bacteriol 155: 1343–1350PubMedGoogle Scholar
  30. Fontana R, Grossato A, Rossi L, Cheng YR, Satta G (1985) Transition from resistance to hypersusceptibility to ß-lactam antibiotics associated with loss of a low-affinity penicillin-binding protein in a S. faecium mutant highly resistant to penicillin. Antimicrob Agents Chemother 28: 678–683PubMedGoogle Scholar
  31. Franceschini N, Galleni M, Frère JM, Oratore A, Amicosante G (1993) A class A ß-lactamase from Pseudomonas stutzeri highly active against monobactams and cefotaxime. Biochem J 292: 697–700PubMedGoogle Scholar
  32. Frère JM (1989) Quantitative relationship between sensitivity to beta-lactam antibiotics and beta-lactamase production in Gram-negative bacteria. I. Steady-state treatment. Biochem Pharmacol 38: 1415–1426PubMedGoogle Scholar
  33. Frère JM, Joris B (1985) Penicillin-sensitive enzymes in peptidoglycan biosynthesis. CRC Crit Rev Microbiol 11: 299–396Google Scholar
  34. Frère JM, Ghuysen JM, Iwatsubo M (1975) Kinetics of interaction between the exocellular DD-carboxypeptidase-transpeptidase from Streptomyces R61 and ß-lactam antibiotics. A choice of models. Eur J Biochem 57: 343–351Google Scholar
  35. Frère JM, Duez C, Ghuysen JM, Vandekerckhove J (1976) Occurrence of a serine residue in the penicillin-binding site of the exocellular DD-carboxypeptidase-transpeptidase from Streptomyces R61. FEBS Lett 70: 257–260PubMedGoogle Scholar
  36. Frère JM, Nguyen-Distèche M, Coyette J, Joris B (1992) Mode of action: interaction with the penicillin-binding proteins. In: Page MI (ed) The chemistry of beta-lactams. Chapman and Hall, Glasgow, pp 148–195Google Scholar
  37. Galleni M, Frère JM (1988) A survey of the kinetic parameters of class C ß-lactamases. I. Penicillins. Biochem J 255: 119–122Google Scholar
  38. Gallen M, Amicosante G, Frère JM (1988) A survey of the kinetic parameters of class C ß-lactamases. II. Cephalosporins and other ß-lactam compounds. Biochem J 255: 123–129Google Scholar
  39. Garcia-Bustos J, Tomasz A (1990) A biological price of antibiotic resistance: major changes in the peptidoglycan structure of penicillin-resistant pneumococci. Proc Natl Acad Sci USA 87: 5415–5419PubMedGoogle Scholar
  40. Ghuysen JM (1968) Use of bacteriolytic enzymes in determination of wall structure and their role in cell metabolism. Bacteriol Rev 32: 425–464PubMedGoogle Scholar
  41. Ghuysen JM (1991) Serine beta-lactamases and penicillin-binding proteins. Annu Rev Microbiol 45: 37–67PubMedGoogle Scholar
  42. Hackbarth CJ, Chambers HF (1989) Methicillin resistant staphylococci: detection methods and treatment of infections. Antimicrob Agents Chemother 33: 995–999PubMedGoogle Scholar
  43. Hancock REW, Siehnel R, Martin N (1990) Outer membrane proteins of Pseudomonas. Mol Microbiol 4: 1069–1075PubMedGoogle Scholar
  44. Hechler U, Van Den Weghe M, Martin HH, Frère JM (1989) Overproduced ß-lactamase and the outer membrane barrier as resistance factors in Serratia marcescens highly resistant to ß-lactamase stable ß-lactam antibiotics. J Gen Microbiol 135: 1275–1290PubMedGoogle Scholar
  45. Hedge PJ, Spratt B (1985a) Amino acid substitutions that reduce the affinity of penicillin-binding protein 3 of E. coli for cephalexin. Eur J Biochem 151: 111–121PubMedGoogle Scholar
  46. Hedge PJ, Spratt BG (1985b) Resistance to beta-lactam antibiotics by re-modelling the active site of an E. coli penicillin-binding protein. Nature 318: 478–480PubMedGoogle Scholar
  47. Herzberg O (1991) Refined crystal structure of ß-lactamase from Staphylococcus aureus PC1 at 2.0 A resolution. J Mol Biol 217: 701–719PubMedGoogle Scholar
  48. Jacob-Dubuisson F, Lamotte-Brasseur J, Dideberg O, Joris B, Frère JM (1991) Arginine 220 is a critical residue for the catalytic mechanism of the Streptomyces albus G ß-lactamase. Protein Eng 4: 811–819PubMedGoogle Scholar
  49. Jacoby GA, Medeiros AA (1991) More extended-spectrum ß-lactamases. Antimicrob Agents Chemother 35: 1697–1704PubMedGoogle Scholar
  50. Jamin M, Adam M, Damblon C, Christiaens L, Frère JM (1991) Accumulation of acyl-enzyme in DD-peptidase-catalysed reactions with analogues of peptide substrates. Biochem J 280: 499–506PubMedGoogle Scholar
  51. Jamin M, Hakenbeck R, Frère JM (1993) Penicillin Binding Protein 2x as a major contributor to intrinsic ß-lactam resistance in Streptococcus pneumoniae. FEBS Letters 331: 101–104PubMedGoogle Scholar
  52. Jarlier V, Nikaido H (1990) Permeability barrier to hydrophilic solutes in Mycobacterium chelonei. J Bacteriol 172: 1418–1423PubMedGoogle Scholar
  53. Joris B, Ghuysen JM, Dive G, Renard A, Dideberg O, Charlier P, Frère JM, Kelly J, Boyington J, Moews P, Knox J (1988) The active-site-serine penicillin-recognizing enzymes as members of the Streptomyces R61 DD-peptidase family. Biochem J 250: 313–324PubMedGoogle Scholar
  54. Joris B, Ledent P, Dideberg O, Fonzé E, Lamotte-Brasseur J, Kelly JA, Ghuysen JM, Frère JM (1991) Comparison of the sequences of class-A beta-lactamases and of the secondary structure elements of penicillin-recognizing proteins. Antimicrob Agents Chemother 35: 2294–2301PubMedGoogle Scholar
  55. Kelly JA, Dideberg O, Charlier P, Wery J, Libert M, Moews P, Knox J, Duez C, Fraipont C, Joris B, Dusart J, Frère JM, Ghuysen JM (1986) On the origin of bacterial resistance to penicillin: comparison of a ß-lactamase and a penicillin target. Science 231: 1429–1431PubMedGoogle Scholar
  56. Laible G, Spratt BG, Hakenbeck R (1991) Interspecies recombinational events during the evolution of altered PBP2x genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Mol Microbiol 5: 1993–2002PubMedGoogle Scholar
  57. Labia R, Morand A, Tiwari K, Sirot J, Sirot D, Petit A (1988) Interactions of new plasmid- mediated ß-lactamase with third-generation cephalosporins. Rev Infect Dis 10: 885–891PubMedGoogle Scholar
  58. Laible G, Spratt BG, Hakenbeck R (1991) Interspecies recombinational events during the evolution of altered PBP2x genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Mol Microbiol 5: 1993–2002PubMedGoogle Scholar
  59. Ledent P, Raquet X, Joris B, Van Beeumen J, Frère JM (1993) A comparative study of class D ß-lactamases. Biochem J 292: 555–562PubMedGoogle Scholar
  60. Lindberg F, Lindquist S, Normark S (1988) Genetic basis of induction and overproduction of chromosomal class I ß-lactamase in nonfastidious Gram-negative bacilli. Rev Infect Dis 10: 782–785PubMedGoogle Scholar
  61. Malhotra KT, Nicholas RA (1992) Substitution of lysine 213 with arginine in penicillin-binding protein 5 of Escherichia coli abolishes D-alanine-carboxypeptidase activity without affecting penicillin binding. J Biol Chem 267: 11386–11391PubMedGoogle Scholar
  62. Matagne A, Misselyn-Bauduin AM, Joris B, Erpicum T, Granier B, Frère JM (1990) The diversity of the catalytic properties of class A ß-lactamases. Biochem J 265: 131–146PubMedGoogle Scholar
  63. Matagne A, Joris B, Van Beeumen J, Frère JM (1991) Ragged N-termini and other variants of class A ß-lactamases analysed by chromatofocusing. Biochem J 273: 503–510PubMedGoogle Scholar
  64. Matagne A, Lamotte-Brasseur J, Frère JM (1993) Interactions between active-site serine ß-lactamases and so-called ß-lactamase-stable antibiotics. Eur J Biochem 217: 61–67PubMedGoogle Scholar
  65. Matthews P, Tomasz A (1990) Insertional inactivation of the mec gene in a transposon mutant of a methicillin-resistant clinical isolate of Staphylococcus aureus. Antimicrob Agents Chemother 34: 1777–1779PubMedGoogle Scholar
  66. Messer J, Reynolds PE (1992) Modified peptidoglycan precursors produced by glycopeptideresistant enterococci. FEMS Microbiol. Lett 94: 195–200Google Scholar
  67. Minnikin DE (1982) Lipids: complex lipids, their chemistry, biosynthesis and roles. In: Ratledge C, Standford J (eds) The biology of mycobacteria. Academic Press, London, pp 95–184Google Scholar
  68. Mirelman D (1979) The biosynthesis and assembly of cell wall peptidoglycan. In: Inouye M (ed) Bacterial outer membranes. Wiley, New York, pp 115–166Google Scholar
  69. Moellering J (1990) The enterococci: an enigma and a continuing therapeutic challenge. Eur J Clin Microbiol Infect Dis 9: 73–74PubMedGoogle Scholar
  70. Munoz R, Dowson CG, Daniels M, Coffey TJ, Martin C, Hakenbeck R, Spratt BG (1992) Genetics of resistance to third generation cephalosporins in clinical isolates of Streptococcus pneumoniae. Mol Microbiol 6: 2461–2465PubMedGoogle Scholar
  71. Nakagawa J, Tamaki S, Tomioka S, Matsuhashi M (1984) Functional biosynthesis of cell wall peptidoglycan by polymorphic bifunctional polypeptides. J Biol Chem 259: 13937–13946PubMedGoogle Scholar
  72. Nikaido H (1989) Outer membrane barrier as a mechanism of antimicrobial resistance. Antimicrob Agents Chemother 33: 1831–1836PubMedGoogle Scholar
  73. Nikaido H (1992) Porins and specific channels of bacterial outer membranes. Mol Microbiol 6: 435–442PubMedGoogle Scholar
  74. Nikaido H, Normark S (1987) Sensitivity of Escherichia coli to various ß-lactams is determined by the interplay of outer membrane permeability and degradation by periplasmic ßlactamase: a quantitative predictive treatment. Mol Microbiol 1: 29–36PubMedGoogle Scholar
  75. Oefner C, Darcy A, Daly JJ, Gubernator K, Charnas RL, Heinze I, Hubschwerlen C, Winkler FK (1990) Refined crystal structure of beta-lactamase from Citrobacter freundii indicates a mechanism for beta-lactam hydrolysis. Nature 343: 284–288PubMedGoogle Scholar
  76. Payne DJ, Amyes SGB (1991) Transferable resistance to extended-spectrum ß-lactams: a major threat or a minor inconvenience? J Antimicrob Chemother 27: 255–261PubMedGoogle Scholar
  77. Pratt RF (1992) ß-Lactamase: inhibition. In: Page MI (ed) The chemistry of ß-lactams. Chapman and Hall, Glasgow, pp 229–271Google Scholar
  78. Pratt RF, Govardhan CP (1984) ß-Lactamase-catalyzed hydrolysis of acyclic depsipeptides and acyl transfer to specific amino aicd acceptors. Proc Natl Acad Sci USA 81: 1302–1306PubMedGoogle Scholar
  79. Rasmussen BA, Gluzman Y, Tally FP (1990) Cloning and sequencing of class A ß-lactamase gene (CCRA) from Bacteroides fragilis TAL3636. Antimicrob Agents Chemother 34: 1590–1592PubMedGoogle Scholar
  80. Reynolds PE (1989) Structure, biochemistry and mechanism of action of glycopeptide antibiotics. Eur J Clin Microbiol Infect Dis 8: 943–950PubMedGoogle Scholar
  81. Samraoui B, Sutton B, Todd R, Artymiuk P, Waley SG, Phillips D (1986) Tertiary structure similarity between a class A ß-lactamase and a penicillin-sensitive D-alanyl-carboxypeptidase-transpeptidase. Nature 320: 378–380PubMedGoogle Scholar
  82. Schockman GD, Barrett JF (1983) Structure, function and assembly of cell walls of Gram-positive bacteria. Annu Rev Microbiol 37: 501–527Google Scholar
  83. Sirot D, Sirot J, Labia R, Morand A, Courvalin P, Darfeuille-Michaud A, Perroux R, Cluzel R (1987) Transferable resistance to third-generation cephalosporins in clinical isolates of Klebsiella pneumoniae: identification of CTX-1, a novel ß-lactamase. J Antimicrob Chemother 20: 323–334PubMedGoogle Scholar
  84. Sougakoff W, Goussard S, Gerbaud G, Courvalin P (1988) Plasmid-mediated resistance to third-generation cephalosporins caused by TEM-type penicillinase genes. Rev Infect Dis 10: 879–884PubMedGoogle Scholar
  85. Sowek JA, Singer SB, Ohringer S, Malley MF, Dougherty TJ, Gougoutas JZ, Bush K (1991) Substitution of lysine at position 104 or 240 of TEM-1 pTZ18R ß-lactamase enhances the effect of serine-164 substitution on hydrolysis or affinity for cephalosporins and the monobactam aztreonam. Biochemistry 30: 3179–3188PubMedGoogle Scholar
  86. Spratt BG (1975) Distinct penicillin-binding proteins involved in the division, elongation and shape of Escherichia coli K12. Proc Natl Acad Sci USA 72: 2999–3003PubMedGoogle Scholar
  87. Spratt BG (1983) Penicillin-binding proteins and the future of beta-lactam antibiotics. J Gen Microbiol 129: 1247–1260PubMedGoogle Scholar
  88. Spratt BG (1988) Hybrid penicillin-binding proteins in penicillin-resistant strains of Neisseria gonorrhoeae. Nature (Lond) 332: 173–176Google Scholar
  89. Spratt BG, Zhang QY, Jones DM, Hutchison A, Brannigan JA, Dowson CG (1989) Recruitment of a penicillin-binding protein gene from Neisseria flavescens during the emergence of penicillin resistance in Neisseria meningitidis. Proc Natl Acad Sci USA 86: 8988–8992PubMedGoogle Scholar
  90. Spratt BG (1983) Penicillin-binding proteins and the future of beta-lactam antibiotics. J Gen Microbiol 129: 1247–1260PubMedGoogle Scholar
  91. Spratt BG, Bowler LD, Zhang QY, Zhou J, Maynard-Smith J (1992) Role of interspecies transfer of chromosomal genes in the evolution of penicillin resistance in pathogenic and commensal Neisseria species. J Mol Evol 34: 115–125PubMedGoogle Scholar
  92. Suzuki E, Hiramatsu K, Yokota T (1992) Survey of methicillin-resistant clinical strains of coagulase-negative staphylococci for mecA gene distribution. Antimicrob Agents Chemother 36: 429–434PubMedGoogle Scholar
  93. Suzuki H, van Heijenoort Y, Tamura T, Mizoguchi J, Hirota Y, van Heijenoort J (1980) In vitro peptidoglycan polymerization catalysed by penicillin-binding protein lb of Escherichia coli. FEBS Lett 110: 245–249PubMedGoogle Scholar
  94. Thompson JS, Malamy MH (1990) Sequencing the gene for imipenem-cefoxitin-hydrolysing enzyme (CfiA) from Bacteroides fragilis TAL2480 reveals strong similarity between CfiA and Bacillus cereus ß-lactamase II. J Bacteriol 172: 2584–2593PubMedGoogle Scholar
  95. Thomson CJ, Amyes SGB (1992) TRC-1: emergence of a clavulanic acid-resistant TEM ß-lactamase in a clinical strain. FEMS Microbiol Lett 91: 113–118Google Scholar
  96. Tipper DJ, Strominger JL (1965) Mechanism of action of penicillins: a proposal based on the structural similarity to acyl-D-alanyl-D-alanine. Proc Natl Acad Sci USA 54: 1131–1141 Ubukata K, Yamashita N, Konno M (1985) Occurrence of ß-lactamase inducible penicillin-binding protein in methicillin-resistant staphylococci. Antimicrob Agents Chemother 27: 851–857Google Scholar
  97. Vedel G, Belaaouaj A, Gilly L, Labia R, Philippon A, Nevot P, Paul G (1992) Clinical isolates of Escherichia coli producing TRI ß-lactamases: novel TEM-enzymes conferring resistance to ß-lactamase inhibitors. J Antimicrob Chemother 30: 449–462PubMedGoogle Scholar
  98. Waley SG (1987) An explicit model for bacterial resistance: application to beta-lactam antibiotics. Microbiol Sci 4: 143–146PubMedGoogle Scholar
  99. Waley SG (1992) ß-Lactamase: mechanism of action. In: Page MI (ed) The chemistry of ß-lactams Chapman and Hall, Glasgow, pp 198–228Google Scholar
  100. Wientjes FB, Nanninga N (1991) On the role of the high molecular weight penicillin-binding proteins in the cell cycle of Escherichia coli. Res Microbiol. 142: 333–344PubMedGoogle Scholar
  101. Wilkin JM, Jamin M, Joris B, Frère JM (1993) The mechanism of action of DD-peptidases. The role of asparagine 161 in the Streptomyces R61 DD-peptidase. Biochem J 293: 195–201PubMedGoogle Scholar
  102. Williams DH, Butcher DW (1981) Binding site of the antibiotic vancomycin for a cell-wall peptide analogue. J Am Chem Soc 103: 5697–5700Google Scholar
  103. Yocum RR, Amanuma H, O’Brien TA, Waxman DJ, Strominger JL (1982) Penicillin is an active site inhibitor for four genera of bacteria. J Bacteriol 149: 1150–1153PubMedGoogle Scholar
  104. Zafaralla G, Mobashery S (1992) Facilitation of the 42—A1 pyrroline tautomerization of carbapenem antibiotics by the highly conserved arginine-244 of class A ß-lactamases during the course of turnover. J Am Chem Soc 114: 1505–1506Google Scholar
  105. Zafaralla G, Manavathu EK, Lerner SA, Mobashery S (1992) Elucidation of the role of arginine-244 in the turnover processes of class A ß-lactamases. Biochemistry 31: 3847–3852PubMedGoogle Scholar
  106. Zimmermann W, Rosselet A (1977) Function of the outer membrane of Escherichia coli as a permeability barrier to beta-lactam antibiotics. Antimicrob Agents Chemother 12: 368–372PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • J. Coyette
  • M. Nguyen-Distèche
  • J. Lamotte-Brasseur
  • B. Joris
  • E. Fonzé
  • J.-M. Frère
    • 1
  1. 1.Centre d’Ingénierie des Protéines et Laboratoire d’Enzymologie, Institut Chimie (B6) au Sart TilmanUniversité de LiègeLiège 1Belgium

Personalised recommendations