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mail : Sandy GRUSS
Bacterial incorporation of exogenous fatty acids and impact on fitness and virulence
I. Bacterial dialog with the environment relies on membrane fatty acids
Membranes are gatekeepers of all living cells. Phospholipids comprise about 40 percent of the membrane; the fatty acids comprising phospholipids determine many of their properties, including membrane fluidity and thickness. These intrinsic properties, plus the indirect consequences of phospholipids on other constituents such as lipid-anchored proteins or sugars, modulate bacterial integrity and the dialogue between bacteria and their environment.
II. Bacterial membranes are flexible and fatty acid replacement is common
The central role of membranes and their fatty acids in bacterial survival has thus spurred development of fatty acid synthesis (FASII) inhibitors as candidate antibacterial targets. It therefore came as a surprise that bacteria can basically sidestep anti-FASII molecules by using environmental fatty acids (eFAs) to replace endogenous fatty acids. Our team, in collaboration with the Poyart (Cochin Hospital) and Trieu-Cuot (Pasteur Institute) labs, uncovered this capacity in the Gram-positive pathogen Streptococcus agalactiae, by showing that a strain deleted for FASII remained infective (Nature, 2009). This is explained, as bacteria are exposed to fatty acids in the host that can be used as replacement when endogenous synthesis is blocked.
III. The case of Staphylococcus aureus
Our lab now focuses on the opportunist pathogen Staphylococcus aureus, a cause of farm animal disease and life-threatening human infections. Anti-FASII drugs have been promoted as a promising venue to fight S. aureus infection, and their development gained support based on claims that fatty acids specific to S. aureus are absolutely required, and cannot be recuperated from the host during infection. Our initial findings proved that FASII can be bypassed by high frequency point mutations that favor the use of eFAs (Nature Communications, 2016). Since then, we identified conditions in which wild type S. aureus overcomes FASII inhibitors without mutations in FASII within a few hours. Full fatty acid replacement upon growth with an anti-FASII occurs after a 6 to 10 hour latency phase. Our current studies of eFA replacement address the following question:
1- Kinetics of eFA incorporation in both phospholipid positions: what, if any specificity of the S. aureus enzymes?
2- What factors define the duration of latency before outgrowth of anti-FASII-refractive S. aureus that use eFA to compensate a FASII block?
3- Can we design a combinatorial strategy that potentiates the action of anti-FASII when combined with other drugs?
Bibliography (2015-2018) :
Boudjemaa R, Cabriel C, Dubois-Brissonnet F, Bourg N, Dupuis G, Gruss A, Leveque-Fort S, Briandet R, Fontaine-Aupart MP and Steenkeste K. (2018) Failure of daptomycin to kill Staphylococcus aureus: impact of bacterial membrane fatty acid composition. Antimicrob Agents Chemother. 62(7). pii: e00023-18. doi: 10.1128/AAC.00023-18.
Morvan C, Halpern D, Kenanian G, Pathania A, Anba-Mondoloni J, Lamberet G, Gruss A and Gloux K (2017) The FASII bypass escape route from FASII inhibitors. Biochimie. DOI: 10.1016/j.biochi.2017.07.004.
Gloux K, Guillemet M, Soler C, Morvan C, Halpern D, Pourcel C, Thien HV, Lamberet G and Gruss A (2017). Clinical relevance of FASII bypass in Staphylococcus aureus. Antimicrob. Agents Chemother. DOI:10.1128/AAC.02515-16.
Joubert L, Dagieu JB, Fernandez A, Derré-Bobillot A, Borezée-Durant E, Fleurot I, Gruss A, Lechardeur D. Visualization of the role of host heme on the virulence of the heme auxotroph Streptococcus agalactiae. Sci Rep. 2017 Jan 16
Morvan C, Halpern D, Kenanian, G, Hays C, Anba-Mondoloni J, Brinster S, Kennedy S, Trieu-Cuot P, Poyart C, Lamberet G, Gloux K, and Gruss A (2016). Environmental Fatty Acids Enable Emergence of Infectious Staphylococcus aureus Resistant to FASII-Targeted Antimicrobials. Nat Comm. DOI: 10.1038/ncomms12944.