Mechanism of Action of New Antiinfectious Agents from Microorganisms

  • Nobuhiro Koyama
  • Hiroshi Tomoda
Conference paper


Currently, drug-resistant bacteria and multidrug-resistant bacteria have spread throughout the world. It is increasingly necessary to develop anti-infectives by a new approach. It is also important to elucidate new molecular targets that are responsible for microbial growth, pathogenicity, and infection. Our research group has conducted original screening systems to search for new bioactive compounds from microorganisms. During these screenings, we discovered some anti-infectives that have unique structures and biological activity. We have investigated target molecules that are involved in their mechanism of action by biochemical and genetic approach. In this study, we describe the latest findings for lariatin A, an anti-mycobacterial agent, and cyslabdan, a potentiator of β-lactam activity against methicillin-resistant Staphylococcus aureus(MRSA).


Actinomycete Strain Microbial Metabolite Lasso Peptide Attractive Drug Target Major Nosocomial Pathogen 
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.



This study was supported in part by Uehara Memorial Foundation and Kakenhi 21310146 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. We express our thanks to Prof. Satoshi Omura and Prof. Yoko Takahashi (Kitasato University) for much help with this study, and to Dr. Yoshio Shibagaki (Kitasato University) for LC–MS/MS analysis. We also thank Dr. Makoto Matsumoto (Otsuka Pharmaceutical Co., Ltd.) for the MIC measurement of M. tuberculosis.


  1. 1.
    NIAID’s Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF). Website: Accessed 18 Jan 2010
  2. 2.
    O’Brien RJ (2001) Global alliance for TB drug development. Scientific blueprint for TB drug development. Tuberculosis 81:1–52CrossRefGoogle Scholar
  3. 3.
    Iwatsuki M, Tomoda H, Uchida R, Gouda H, Hirono S, Kobayashi S, Omura S (2006) Lariatins, antimycobacterial peptides produced by Rhodococcussp. K01-B-0171, have a lasso structure. J Am Chem Soc 128:7486–7491CrossRefPubMedGoogle Scholar
  4. 4.
    Iwatsuki M, Uchida R, Takakusagi Y, Matsumoto A, Jiang CL, Takahashi Y, Arai M, Kobayashi S, Matsumoto M, Inokoshi J, Tomoda H, Omura S (2007) Lariatins, novel anti-mycobacterial peptides with a lasso structure, produced by Rhodococcus jostiiK01-B0171. J Antibiot (Tokyo) 60:357–363CrossRefGoogle Scholar
  5. 5.
    Iwatsuki M, Koizumi Y, Gouda H, Hirono S, Tomoda H, Omura S (2009) Lys17 in the ‘lasso’ peptide lariatin A is responsible for anti-mycobacterial activity. Bioorg Med Chem Lett 19:2888–2890CrossRefPubMedGoogle Scholar
  6. 6.
    Delgado M, Rintoul M, Farias R, Salomon R (2001) Escherichia coliRNA polymerase is the target of the cylcopeptide antibiotic microcin J25. J Bacteriol 183:4543–4550CrossRefPubMedGoogle Scholar
  7. 7.
    Yuzenkova J, Delgado M, Nechaev S, Savalia D, Epshtein V, Artsimovitch I, Mooney R, Landick R, Farias R, Salomon R, Severinov K (2002) Mutations of bacterial RNA polymerase leading to resistance to microcin J25. J Biol Chem 277:50867–50875CrossRefPubMedGoogle Scholar
  8. 8.
    Mukhopadhyay J, Sineva E, Knight J, Levy R, Ebright R (2004) Antibacterial peptide microcin J25 inhibits transcription by binding within, and obstructing, the RNA polymerase secondary channel. Mol Cell 14:739–751CrossRefPubMedGoogle Scholar
  9. 9.
    Adelman K, Yuzenkova J, La Porta A, Zenkin N, Lee J, Lis J, Borukhov S, Wang M, Severinov K (2004) Molecular mechanism of transcription inhibition by peptide antibiotic microcin J25. Mol Cell 14:753–762CrossRefPubMedGoogle Scholar
  10. 10.
    Kuznedelov K, Semenova E, Knappe TA, Mukhamedyarov D, Srivastava A, Chatterjee S, Ebright RH, Marahiel MA, Severinov K (2011) The antibacterial threaded-lasso peptide capistruin inhibits bacterial RNA polymerase. J Mol Biol. doi:10.1016/j.jmb.2011.02.060Google Scholar
  11. 11.
    Wang J, Soisson SM, Young K et al (2006) Platensimycin is a selective FabF inhibitor with potent antibiotics properties. Nature 441:358–361CrossRefPubMedGoogle Scholar
  12. 12.
    Cook TM, Brown KG, Boyle JV, Goss WA (1966) Bacterial action of nalidixic acid on Bacillus subtilis. J Bacteriol 92:1510–1514PubMedGoogle Scholar
  13. 13.
    Klann AG, Belanger AE, Abanes-De M, Lee JY, Hatfull GF (1988) Characterization of the dnaGlocus in Mycobacterium smegmatisreveals linkage of DNA replication and cell division. J Bacteriol 180:65–72Google Scholar
  14. 14.
    Grompe M, Versalovic J, Koeuth T, Lupski JR (1991) Mutations in the Escherichia coli dnaGgene suggest coupling between DNA replication and chromosome partitioning. J Bacteriol 173:1268–1278PubMedGoogle Scholar
  15. 15.
    Lonetto M, Gribskov M, Gross CA (1992) The sigma 70 family: sequence conservation and evolutionary relationships. J Bacteriol 174:3843–3849PubMedGoogle Scholar
  16. 16.
    Buck M, Gallegos MT, Studholme DJ, Guo Y, Gralla JD (2000) The bacterial enhancer-dependent sigma 54 (SigN) transcription factor. J Bacteriol 182:4129–4136CrossRefPubMedGoogle Scholar
  17. 17.
    Waagmeester A, Thompson J, Reyrat J-M (2005) Identifying sigma factors in Mycobacterium smegmatisby comparative genome analysis. Trends Microbiol 13:505–509CrossRefPubMedGoogle Scholar
  18. 18.
    Rodrigue S, Provvedi R, Jacques P-E, Gaudreau L, Manganelli R (2006) The factors of Mycobacterium tuberculosis. FEMS Microbiol Rev 30:926–941CrossRefPubMedGoogle Scholar
  19. 19.
    Yuzhakov A, Kelman Z, O’Donnell M (1999) Trading places on DNA: a three-point switch underles primes handoff from primase to the replicative DNA polymerase. Cell 96:153–163CrossRefPubMedGoogle Scholar
  20. 20.
    Hegde SP, Qin M-H, Li X-H, Atkinson MAL, Clark AJ, Rajagopalan M, Madiraju MVVS (1996) Interactions of RecF protein with RecO, RecR, and single-stranded DNA binding proteins reveal roles for the RecF-RecO-RecR complex in DNA repair and recombination. Proc Natl Acad Sci USA 93(25):14468–14473CrossRefPubMedGoogle Scholar
  21. 21.
    Anderson DG, Kowalczykowski SC (1998) SSB protein controls RecBCD enzyme nuclease activity during unwinding: a new role for looped intermediates. J Mol Biol 282:275–285CrossRefPubMedGoogle Scholar
  22. 22.
    Trovcević Z, Petranović M, Brcić-Kostić K, Petranović D, Lers N, Salaj-Smic E (1991) A possible interaction of single-standed binding protein and RecA protein during post-ultraviolet DNA synthesis. Biochimie 73:515–517CrossRefPubMedGoogle Scholar
  23. 23.
    Lu D, Keck JK (2008) Structural basis of Escherichia colisingle-stranded DNA binding protein stimulation of exonuclease I. Proc Natl Acad Sci USA 105:9169–9174CrossRefPubMedGoogle Scholar
  24. 24.
    Tomasz A (1994) Multiple-antibiotic resistant pathogenic bacteria. N Engl J Med 330:1247–1251CrossRefPubMedGoogle Scholar
  25. 25.
    Hiramatsu K, Hanaki H, Ino T, Yabuta K, Oguri T, Tenover FC (1997) Methicillin-resistant Staphylococcus aureusclinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother 40:135–136CrossRefPubMedGoogle Scholar
  26. 26.
    Centers for Disease Control and Prevention (1997) Staphylococcus aureuswith reduced susceptibility to vancomycin: United States. MMWR Morb Mortal Wkly Rep 46:765–766Google Scholar
  27. 27.
    Omura S (1999) Antiinfective drugs into the 21st century. Nippon Saikingaku Zasshi 54:795–813 (in Japanese)CrossRefPubMedGoogle Scholar
  28. 28.
    Fukumoto A, Kim YP, Matsumoto A, Takahashi Y, Shiomi K, Tomoda H, Omura S (2008) Cyslabdan, a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus, produced by Streptomycessp. K04-0144. I. Taxonomy, fermentation, isolation and structural elucidation. J Antibiot (Tokyo) 61:1–6CrossRefGoogle Scholar
  29. 29.
    Fukumoto A, Kim YP, Hanaki H, Shiomi K, Tomoda H, Omura S (2008) Cyslabdan, a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus, produced by Streptomycessp. K04-0144. II. Biological activities. J Antibiot (Tokyo) 61:7–10CrossRefGoogle Scholar
  30. 30.
    Berger-Bächi B, Barberis-Maino L, Strässle A, Kayser FH (1989) FemA, a host-mediated factor essential for methicillin resistance in Staphylococcus aureus: molecular cloning and characterization. Mol Gen Genet 219:263–269CrossRefPubMedGoogle Scholar
  31. 31.
    Maidhof H, Reinicke B, Blümel P, Berger-Bächi B, Labischinski H (1991) femA, which encodes a factor essential for expression of methicillin resistance, affects glycine content of peptidoglycan in methicillin-resistant and methicillin-susceptible Staphylococcus aureusstrains. J Bacteriol 173:3507–3513PubMedGoogle Scholar
  32. 32.
    Schneider T, Senn MM, Berger-Bächi B, Tossi A, Sahl HG, Wiedemann I (2004) In vitro assembly of a complete, pentaglycine interpeptide bridge containing cell wall precursor (lipid II-Gly5) of Staphylococcus aureus. Mol Microbiol 53:675–685CrossRefPubMedGoogle Scholar
  33. 33.
    Strandén AM, Ehlert K, Labischinski H, Berger-Bächi B (1997) Cell wall monoglycine cross-bridges and methicillin hypersusceptibility in a femAB null mutant of methicillin-resistant Staphylococcus aureus. J Bacteriol 179:9–16PubMedGoogle Scholar
  34. 34.
    Tomasz A (2000) The staphylococcal cell wall. In: Fischetti VA, Novick RP, Ferretti JJ, Portnoy DA, Rood JI (eds) Gram-positive pathogens. American Society for Microbiology, Washington, pp 463–470Google Scholar
  35. 35.
    de Jonge BL, Chang YS, Gage D, Tomasz A (1992) Peptidoglycan composition in heterogeneous Tn551 mutants of a methicillin-resistant Staphylococcus aureusstrain. J Biol Chem 267:11255–11259PubMedGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  1. 1.Graduate School of Pharmaceutical SciencesKitasato UniversityTokyoJapan

Personalised recommendations