Abstract
Anaerobic bacteria are the oldest terrestrial creatures. They occur ubiquitously in soil and in the intestine of higher organisms and play a major role in human health, ecology, and industry. However, until lately no antibiotic or any other secondary metabolite has been known from anaerobes. Mining the genome sequences of Clostridium spp. has revealed a high prevalence of putative biosynthesis genes (PKS and NRPS), and only recently the first antibiotic from the anaerobic world, closthioamide, has been isolated from the cellulose degrading bacterium Clostridium cellulolyticum. The successful genetic induction of antibiotic biosynthesis in an anaerobe encourages further investigations of obligate anaerobes to tap their hidden biosynthetic potential.
Similar content being viewed by others
References
Bahl H, Dürre P (2001) Clostridia: biotechnology and medical applications. Wiley-VCH, Weinheim
Baltz RH (2006) Molecular engineering approaches to peptide, polyketide and other antibiotics. Nat Biotechnol 24(12):1533–1540
Behnken S, Hertweck C (2012) Cryptic polyketide synthase genes in non-pathogenic Clostridium spp. PLoS One 7(1):e29609
Behnken S, Lincke T, Kloss F, Ishida K, Hertweck C (2012) Antiterminator overexpression discloses large family of cryptic polythioamides in an anaerobic bacterium. Angew Chem Int Ed 51(10):2425–2428
Bergmann S, Funk AN, Scherlach K, Schroeckh V, Shelest E, Horn U, Hertweck C, Brakhage AA (2010) Activation of a silent fungal polyketide biosynthesis pathway through regulatory cross talk with a cryptic nonribosomal peptide synthetase gene cluster. Appl Environ Microbiol 76(24):8143–8149
Blunt JW, Copp BR, Munro MH, Northcote PT, Prinsep MR (2010) Marine natural products. Nat Prod Rep 27:165–237
Bode HB (2009) Entomopathogenic bacteria as a source of secondary metabolites. Curr Opin Chem Biol 13(2):224–230
Bode HB, Müller R (2005) The impact of bacterial genomics on natural product research. Angew Chem Int Ed Engl 44:6828–6846
Bruggemann H, Gottschalk G (2008) Comparative genomics of clostridia: link between the ecological niche and cell surface properties. Ann N Y Acad Sci 1125:73–81
Chambers HF (1997) Methillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev 10(4):781–791
Clardy J, Fischbach MA, Walsh CT (2006) New antibiotics from bacterial natural products. Nat Biotechnol 24(2):1541–1550
Corbell N, Loper JE (1995) A global regulator of secondary metabolite production in Pseudomonas fluorescens Pf-5. J Bacteriol 177(21):6230–6236
Davison J (1999) Genetic exchange between bacteria in the environment. Plasmid 42(2):73–91
Desvaux M (2005) Clostridium cellulolyticum: model organism of mesophilic cellulolytic clostridia. FEMS Microbiol Rev 29:741–764
Donadio S, Monciardini P, Sosio M (2007) Polyketide synthases and nonribosomal peptide synthetases: the emerging view from bacterial genomics. Nat Prod Rep 24:1073–1109
Donadio S, Maffioli S, Monciardini P, Sosio M, Jabes D (2010) Antibiotic discovery in the twenty-first century: current trends and future perspectives. J Antibiot 63(8):423–430
Girbal L, von Abendroth G, Winkler M, Benton PM, Meynial-Salles I, Croux C, Peters JW, Happe T, Soucaille P (2005) Homologous and heterologous overexpression in Clostridium acetobutylicum and characterization of purified clostridial and algal Fe-only hydrogenases with high specific activities. Appl Environ Microbiol 71(5):2777–2781
Gross H (2007) Strategies to unravel the function of orphan biosynthesis pathways: recent examples and future prospects. Appl Microbiol Biotechnol 75(2):267–277
Hatheway CL (1990) Toxigenetic clostridia. Clin Microbiol Rev 31:66–98
Heap JH, Pennington OJ, Cartman ST, Minton NP (2009) A modular system for Clostridium shuttle plasmids. J Microbiol Methods 78:79–85
Heap JH, Kuehne SA, Ehsaan M, Cartman ST, Cooksley CM, Scott JC, Minton NP (2010) The ClosTron: mutagenesis in Clostridium refined and streamlined. J Microbiol Methods 80:49–55
Hertweck C (2009a) The biosynthetic logic of polyketide diversity. Angew Chem Int Ed 48:4688–4716
Hertweck C (2009b) Hidden biosynthetic treasures brought to light. Nat Chem Biol 5(7):450–452
Hochmuth T, Piel J (2009) Polyketide synthases of bacterial symbionts in sponges—evolution-based applications in natural products research. Phytochemistry 70(15–16):1841–1849
Ishida K, Lincke T, Behnken S, Hertweck C (2010) Induced biosynthesis of cryptic polyketide metabolites in a Burkholderia thailandensis quorum sensing mutant. J Am Chem Soc 132(40):13966–13968
Janssen H, Döring C, Ehrenreich A, Voigt B, Hecker M, Bahl H, Fischer R-F (2010) A proteomic and transcriptional view of acidogenic and solventogenic steady-state cells of Clostridium acetobutylicum in a chemostat culture. Appl Microbiol Biotechnol 87:2209–2226
Jenke-Kodama H, Sandmann A, Muller R, Dittmann E (2005) Evolutionary implications of bacterial polyketide synthases. Mol Biol Evol 22(10):2027–2039
Jennert KCB, Tardif C, Young DI, Young M (2000) Gene transfer to Clostridium cellulolyticum ATCC 35319. Microbiol 146:3071–3080
Jeschke P, Harder A, Etzel W, Gau W, Thielking G, Bonse G, Iinuma K (2001) Synthesis and anthelmintic activity of thioamide analogues of cyclic octadepsipeptides such as PF1022A. Pest Manag Sci 57:1000–1006
Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, Mcdougal LK, Carey RB, Fridkin SK, Active Bacterial Core surveillance (ABCs) MRSA Investigators (2007) Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298(15):1763–1771
Kloss F, Lincke T, Hertweck C (2011) Highly Efficient total synthesis of the Clostridium-derived anti-MRSA antibiotic closthioamide. Eur J Org Chem 2011:1429–1431
Kuehne SA, Heap JT, Cooksley CM, Cartman ST, Minton NP (2011) ClosTron-mediated engineering of Clostridium. Meth Mol Biol 765:389–407
Lincke T, Behnken S, Ishida K, Roth M, Hertweck C (2010) Closthioamide: an unprecedented polythioamide antibiotic from the strictly anaerobic bacterium Clostridium cellulolyticum. Angew Chem Int Ed 122:2055–2057
Mingardon F, Chanal A, Tardif C, Fierobe HP (2011) The issue of secretion in heterologous expression of Clostridium cellulolyticum cellulase-encoding genes in Clostridium acetobutylicum ATCC 824. Appl Environ Microbiol 77(9):2831–2838
Nguyen T, Ishida K, Jenke-Kodama H, Dittmann E, Gurgui C, Hochmuth T, Taudien S, Platzer M, Hertweck C, Piel J (2008) Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection. Nat Biotechnol 26(2):225–233
Nishida T, Orikasa Y, Ito Y, Yu R, Yamada A, Watanabe K, Okuyama H (2006) Escherichia coli engineered to produce eicosapentaenoic acid becomes resistant against oxidative damages. FEBS Lett 580(11):2731–2735
Osada H, Hertweck C (2009) Exploring the chemical space of microbial natural products. Curr Opin Chem Biol 13(2):133–134
Papoutsakis ET (2008) Engineering solventogenic clostridia. Curr Opion Biotechnol 19:420–429
Paredes CJ, Alasker KV, Papoutsakis ET (2005) A comparative genomic view of clostridial sporulation and physiology. Nat Rev Microbiol 3:969–978
Partida-Martinez LP, Hertweck C (2005) Pathogenic fungus harbours endosymbiotic bacteria for toxin production. Nature 437:884–888
Petidemange E, Caillet F, Giallo J, Gaudin C (1984) Clostridium cellulolyticum sp. nov., a cellulolytic, mesophilic species from decayed grass. Int J Sys Bacteriol 34:155–159
Piel J (2010) Biosynthesis of polyketides by trans-AT polyketide synthases. Nat Prod Rep 27(7):996–1047
Scherlach K, Hertweck C (2009) Triggering cryptic natural product biosynthesis in microorganisms. Org Biomol Chem 7:1753–1760
Schmidt EW (2008) Trading molecules and tracking targets in symbiotic interactions. Nat Chem Biol 4:466–473
Schwarzer D, Finking R, Marahiel MA (2003) Nonribosomal peptides: from genes to products. Nat Prod Rep 20:275–287
Seedorf H, Fricke WF, Veith B, Brüggemann H, Liesegang H, Strittmatter A, Buckel W, Hinderberger J, Hagemeier C, Thauer RK, Gottschalk G (2008) The genome of Clostridium kluyveri, a strict anaerobe with unique metabolic features. Proc Natl Acad Sci 105(6):2128–2133
Shulse CN, Allen EE (2011) Widespread occurrence of secondary lipid biosynthesis potential in microbial lineages. PLoS One 6(5):e20146
Sturgen NO, Casida JLE (1962) Antibiotic production by anaerobic bacteria. Appl Microbiol 10:55–59
Teta R, Gurgui M, Helfrich EJ, Kunne S, Schneider A, Van Echten-Deckert G, Mangoni A, Piel J (2010) Genome mining reveals trans-AT polyketide synthase directed antibiotic biosynthesis in the bacterial phylum bacteroidetes. ChemBioChem 11(18):2506–2512
Tummala SB, Welker NE, Papoutsakis ET (1999) Development and characterization of a gene expression reporter system for Clostridium acetobutylicum ATCC 824. Appl Environ Microbiol 65(9):3793–3799
Van Lanen SG, Shen B (2008) Advances in polyketide synthase structure and mechanism. Curr Opin Drug Discov Develop 11:186–195
Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WRJ, Sacchettini JC (2007) Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med 204:73–78
Weber T, Welzel K, Pelzer S, Vente A, Wohlleben W (2003) Exploiting the genetic potential of polyketide producing streptomycetes. J Biotechnol 106:221–232
Weingart OG, Schreiber T, Mascher C, Pauly D, Dorner MB, Berger TFH, Egger C, Gessler F, Loessner MJ, Avondet M-A, Dorner BG (2010) The case of botulinum toxin in milk: experimental data. Appl Environ Microbiol 76(10):3293–3300
Weissman KJ, Müller R (2010) Myxobacterial secondary metabolites: bioactivities and modes-of-action. Nat Prod Rep 27:1276–1295
Wilkinson B, Micklefield J (2007) Mining and engineering natural-product biosynthetic pathways. Nat Chem Biol 3(7):379–386
Winter JM, Behnken S, Hertweck C (2011) Genomics-inspired discovery of natural products. Curr Opin Chem Biol 15(1):22–31
Xu D, Seghezzi N, Esnault C, Virolle M-J (2010) Repression of antibiotic production and sporulation in Streptomyces coelicolor by overexpression of a TetR family transcriptional regulator. Appl Environ Microbiol 76(23):7741–7753
Zerikly M, Challis GL (2009) Strategies for the discovery of new natural products by genome mining. ChemBioChem 10:625–633
Acknowledgments
This work was supported by the “Pakt für Forschung und Innovation” of the Free State of Thuringia and the Federal Ministry of Science and Technology (BMBF, Germany), and the International Leibniz Research School for Biomolecular and Microbial Interactions (ILRS), as part of the excellence graduate school Jena School for Microbial Communication (JSMC). We thank Dr. Sacha Pidot for critically reading the manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Behnken, S., Hertweck, C. Anaerobic bacteria as producers of antibiotics. Appl Microbiol Biotechnol 96, 61–67 (2012). https://doi.org/10.1007/s00253-012-4285-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-012-4285-8