Abstract
Antimicrobial drugs targeting the reportedly essential type II fatty acid synthesis (FASII) pathway1,2,3,4,5 have been recently acclaimed for their efficacy against infections caused by multiresistant Gram-positive bacteria6,7,8. Our findings show that the strategy for antibiotic development based on FASII pathway targets is fundamentally flawed by the fact that exogenous fatty acids fully bypass inhibition of this pathway in both in vitro and in vivo conditions. We demonstrate that major Gram-positive pathogens—such as streptococci, pneumococci, enterococci and staphylococci—overcome drug-induced FASII pathway inhibition when supplied with exogenous fatty acids, and human serum proves to be a highly effective source of fatty acids. For opportunist pathogen Streptococcus agalactiae, growth in serum leads to an overall decrease of FASII gene expression. No antibiotic inhibitor could have a stronger effect than the inactivation of the target gene, so we challenged the role of FASII using deletion mutants. Our results unequivocally show that the FASII target enzymes are dispensable in vivo during S. agalactiae infection. The results of this study largely compromise the use of FASII-based antimicrobials for treating sepsis caused by Gram-positive pathogens.
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References
Altabe, S., Lopez, P. & de Mendoza, D. Isolation and characterization of unsaturated fatty acid auxotrophs of Streptococcus pneumoniae and Streptococcus mutans . J. Bacteriol. 189, 8139–8144 (2007)
Marrakchi, H., Zhang, Y. M. & Rock, C. O. Mechanistic diversity and regulation of Type II fatty acid synthesis. Biochem. Soc. Trans. 30, 1050–1055 (2002)
Price, A. C. et al. Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J. Biol. Chem. 276, 6551–6559 (2001)
Wright, H. T. & Reynolds, K. A. Antibacterial targets in fatty acid biosynthesis. Curr. Opin. Microbiol. 10, 447–453 (2007)
Zhang, Y. M., White, S. W. & Rock, C. O. Inhibiting bacterial fatty acid synthesis. J. Biol. Chem. 281, 17541–17544 (2006)
Wang, J. et al. Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441, 358–361 (2006)
Wang, J. et al. Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties. Proc. Natl Acad. Sci. USA 104, 7612–7616 (2007)
Zhang, Y. M. & Rock, C. O. Membrane lipid homeostasis in bacteria. Nat. Rev. Microbiol. 6, 222–233 (2008)
Campbell, J. W. & Cronan, J. E. Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery. Annu. Rev. Microbiol. 55, 305–332 (2001)
Johnsson, T., Nikkila, P., Toivonen, L., Rosenqvist, H. & Laakso, S. Cellular fatty acid profiles of Lactobacillus and Lactococcus strains in relation to the oleic acid content of the cultivation medium. Appl. Environ. Microbiol. 61, 4497–4499 (1995)
Altenbern, R. A. Cerulenin-inhibited cells of Staphylococcus aureus resume growth when supplemented with either a saturated or an unsaturated fatty acid. Antimicrob. Agents Chemother. 11, 574–576 (1977)
Kankaanpaa, P., Yang, B., Kallio, H., Isolauri, E. & Salminen, S. Effects of polyunsaturated fatty acids in growth medium on lipid composition and on physicochemical surface properties of lactobacilli. Appl. Environ. Microbiol. 70, 129–136 (2004)
Yamamoto, Y. et al. The group B streptococcus NADH oxidase Nox-2 is involved in fatty acid biosynthesis during aerobic growth and contributes to virulence. Mol. Microbiol. 62, 772–785 (2006)
Campbell, J. W. & Cronan, J. E. Escherichia coli FadR positively regulates transcription of the fabB fatty acid biosynthetic gene. J. Bacteriol. 183, 5982–5990 (2001)
Lai, C. Y. & Cronan, J. E. Beta-ketoacyl-acyl carrier protein synthase III (FabH) is essential for bacterial fatty acid synthesis. J. Biol. Chem. 278, 51494–51503 (2003)
Fozo, E. M. & Quivey, R. G. The fabM gene product of Streptococcus mutans is responsible for the synthesis of monounsaturated fatty acids and is necessary for survival at low pH. J. Bacteriol. 186, 4152–4158 (2004)
Fozo, E. M., Scott-Anne, K., Koo, H. & Quivey, R. G. Role of unsaturated fatty acid biosynthesis in virulence of Streptococcus mutans . Infect. Immun. 75, 1537–1539 (2007)
Nakamura, T. et al. Serum fatty acid levels, dietary style and coronary heart disease in three neighbouring areas in Japan: the Kumihama study. Br. J. Nutr. 89, 267–272 (2003)
Raetz, C. R., Reynolds, C. M., Trent, M. S. & Bishop, R. E. Lipid A modification systems in gram-negative bacteria. Annu. Rev. Biochem. 76, 295–329 (2007)
Bhargava, H. N. & Leonard, P. A. Triclosan: applications and safety. Am. J. Infect. Control 24, 209–218 (1996)
Glaser, P. et al. Genome sequence of Streptococcus agalactiae, a pathogen causing invasive neonatal disease. Mol. Microbiol. 45, 1499–1513 (2002)
Hamilton, J. A. How fatty acids bind to proteins: the inside story from protein structures. Prostaglandins Leukot. Essent. Fatty Acids 67, 65–72 (2002)
Moellering, R. C. & Weinberg, A. N. Studies on antibiotic syngerism against enterococci. II. Effect of various antibiotics on the uptake of 14 C-labeled streptomycin by enterococci. J. Clin. Invest. 50, 2580–2584 (1971)
Berger, J. & Moller, D. E. The mechanisms of action of PPARs. Annu. Rev. Med. 53, 409–435 (2002)
Staels, B., Maes, M. & Zambon, A. Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease. Nature Clin. Pract. Cardiovasc. Med. 5, 542–553 (2008)
Scortti, M. et al. Coexpression of virulence and fosfomycin susceptibility in Listeria: molecular basis of an antimicrobial in vitro-in vivo paradox. Nature Med. 12, 515–517 (2006)
Gill, C. J. et al. In vivo activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L-749,345). Antimicrob. Agents Chemother. 42, 1996–2001 (1998)
Tomita, Y., Miyake, N. & Yamanaka, S. Lipids in human parotid saliva with regard to caries experience. J. Oleo Sci. 57, 115–121 (2008)
Yamamoto, Y. et al. Respiration metabolism of group B streptococcus is activated by environmental haem and quinone and contributes to virulence. Mol. Microbiol. 56, 525–534 (2005)
Dramsi, S. et al. Assembly and role of pili in group B streptococci. Mol. Microbiol. 60, 1401–1413 (2006)
Maguin, E., Prevost, H., Ehrlich, S. D. & Gruss, A. Efficient insertional mutagenesis in lactococci and other gram-positive bacteria. J. Bacteriol. 178, 931–935 (1996)
Acknowledgements
We are grateful to I. Tardieux, P. Bouloc and L. Gutmann for critical reading and discussion of the manuscript, and P. Gaudu and Y. Yamamoto for discussion. We thank A. Bouaboud for technical assistance, and C. Fievet and N. Hennuye for mouse serum fatty acid analyses and advice. This work was supported by research funding from the French Agence Nationale de la Recherche (ANR, StrepRespire Project), INSERM, INRA, Université Paris Descartes, and the Institut Pasteur. S.B. was a recipient of a post-doctoral fellowship from the ANR StrepRespire Project.
Author Contributions S.B. performed MIC experiments, genetic constructions, phenotypic characterization of the mutants. G.L. performed fatty acid determination. C.P. and S.B. conducted in vivo experiments. B.S. participated in the design of in vivo triglyceride and fatty acid depletion experiments. C.P., P.T.-C. and A.G. conceptualized and designed the study. C.P. and A.G. wrote the manuscript with contributions from S.B., G.L. and P.T.-C.
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Brinster, S., Lamberet, G., Staels, B. et al. Type II fatty acid synthesis is not a suitable antibiotic target for Gram-positive pathogens. Nature 458, 83–86 (2009). https://doi.org/10.1038/nature07772
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DOI: https://doi.org/10.1038/nature07772
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