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Staphylococcus aureus se met transitoirement en dormance pour utiliser les acides gras de l'hôte et échapper à une inhibition par un anti-FASII : quel signal active son réveil ?

Abstract : Treatment of infections caused by multidrug-resistant bacteria is a major medical challenge of the 21st century, which has stimulated the search for essential bacterial functions as potential antimicrobial drug targets. The fatty acid synthesis (FASII) pathway enzymes are considered essential, and numerous antibiotics called (anti-FASII), have been developed to eliminate pathogens of the Firmicutes phylum. However, our laboratory has shown that several pathogens bypass FASII inhibitors by incorporating exogenous fatty acids (FAs), which are abundant in the host (in blood, organs and foods). FASII bypass thus compromises the use of FASII-based antibiotics. The status of the major pathogen, Staphylococcus aureus, has remained in debate. S. aureus synthesizes an FA not produced by the host and according to the literature, is required and would not be available in the host. However, work in my lab showed that indeed bypasses FASII. The goal of my research project is to understand the mechanisms used by S. aureus to bypass FASII antibiotics. Two mechanisms are highlighted: I- High frequency mutations of the fabD gene allow S. aureus to use exogenous FAs; our study indicates that higher availability of ACP in these mutants facilitates FA utilization. II- A strategy without detectable mutation occurs in the presence of host fluids such as serum. It comprises a first "dormancy" step of about 8 to 10 hours, followed by outgrowth; FAs are incorporated throughout these steps. The latency phase appears to be due to a division block, during which cells undergo morphological changes. During "normal" growth recovery, S. aureus freely uses exogenous FAs and remains insensitive to anti-FASII. Using « time-lapse » microscopic study, we showed in our test conditions that about 3% of the bacterial population adapted to FASII antibiotics. Ours results point to an adaptation mechanism in which serum decreases bacterial stress, leading to increased availability of ACP and exogenous FAs. These substrates can then be used for phospholipid synthesis. These results resolve the debate by showing that S. aureus can replace endogenous FAs with exogenous FAs when FASII is blocked. Contrary to current dogma, FASII is not essential in S. aureus. To identify the loci involved in adaptation to anti-FASII, we performed proteomic analyses and also screened a S. aureus mutant library. Functions of stress response, cell division, and lipid metabolism appear to be involved in this adaptation. To conclude, this study clarified the steps leading to S. aureus adaptation to FASII antibiotics. Although our results show that S. aureus bypasses anti-FASII, a combinatorial approach could be considered in which FASII antibiotics could be coupled to a second inhibitor that would prevent exit from the dormancy.
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Gérald Kénanian. Staphylococcus aureus se met transitoirement en dormance pour utiliser les acides gras de l'hôte et échapper à une inhibition par un anti-FASII : quel signal active son réveil ?. Bactériologie. Université Paris Saclay (COmUE), 2018. Français. ⟨NNT : 2018SACLS242⟩. ⟨tel-02937441⟩

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