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Type II fatty acid synthesis is not a suitable antibiotic target for Gram-positive pathogens

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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Figure 1: Impact of serum addition on S. agalactiae FASII gene expression and growth.
Figure 2: Cellular fatty acid composition and in vivo virulence assays.

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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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Correspondence to Alexandra Gruss or Claire Poyart.

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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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