title: Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials.
abstract: The bacterial pathway for fatty acid biosynthesis, FASII, is a target for development of new anti-staphylococcal drugs. This strategy is based on previous reports indicating that self-synthesized fatty acids appear to be indispensable for Staphylococcus aureus growth and virulence, although other bacteria can use exogenous fatty acids to compensate FASII inhibition. Here we report that staphylococci can become resistant to the FASII-targeted inhibitor triclosan via high frequency mutations in fabD, one of the FASII genes. The fabD mutants can be conditional for FASII and not require exogenous fatty acids for normal growth, and can use diverse fatty acid combinations (including host fatty acids) when FASII is blocked. These mutants show cross-resistance to inhibitors of other FASII enzymes and are infectious in mice. Clinical isolates bearing fabD polymorphisms also bypass FASII inhibition. We propose that fatty acid-rich environments within the host, in the presence of FASII inhibitors, might favour the emergence of staphylococcal strains displaying resistance to multiple FASII inhibitors.
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas 78350, France.
authors.forename: Claire
authors.identifier: http://orcid.org/0000-0001-8435-0523
authors.initials: C
authors.lastname: Morvan
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas 78350, France.
authors.forename: David
authors.initials: D
authors.lastname: Halpern
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas 78350, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Kénanian
authors.affiliation: 'Barriers and Pathogens' Team, INSERM U 1016, Institut Cochin, Paris F-75014, France.|CNRS UMR 8104, Paris F-75014, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris F-75014, France.|Hôpitaux Universitaires Paris Centre Cochin-Hôtel Dieu-Broca, Assistance Publique Hôpitaux de Paris, Paris F-75014, France.
authors.forename: Constantin
authors.initials: C
authors.lastname: Hays
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas 78350, France.
authors.forename: Jamila
authors.initials: J
authors.lastname: Anba-Mondoloni
authors.affiliation: 'Barriers and Pathogens' Team, INSERM U 1016, Institut Cochin, Paris F-75014, France.|CNRS UMR 8104, Paris F-75014, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris F-75014, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brinster
authors.affiliation: Metagenopolis-Micalis UMR 1319, Jouy en Josas 78352, France.
authors.forename: Sean
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Biology of Gram-positive Pathogens Unit. Institut Pasteur 25-28 rue du docteur Roux, Paris 75015, France.|CNRS ERL3526, Paris 75015, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trieu-Cuot
authors.affiliation: 'Barriers and Pathogens' Team, INSERM U 1016, Institut Cochin, Paris F-75014, France.|CNRS UMR 8104, Paris F-75014, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris F-75014, France.|Hôpitaux Universitaires Paris Centre Cochin-Hôtel Dieu-Broca, Assistance Publique Hôpitaux de Paris, Paris F-75014, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Poyart
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas 78350, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Lamberet
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas 78350, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Gloux
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas 78350, France.
authors.forename: Alexandra
authors.identifier: http://orcid.org/0000-0001-7426-5229
authors.initials: A
authors.lastname: Gruss
mesh_terms: D051080:Acyl-Carrier Protein S-Malonyltransferase / Q000378:metabolism; D000483:Alleles; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D003001:Cloning, Molecular; D024881:Drug Resistance, Bacterial; D029968:Escherichia coli Proteins / Q000378:metabolism; D054889:Fatty Acid Synthase, Type II / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005816:Genetic Complementation Test; D050155:Lipogenesis; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D013211:Staphylococcus aureus / Q000378:metabolism*; D014260:Triclosan / Q000494:pharmacology; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D005227:Fatty Acids; D014260:Triclosan; D051080:Acyl-Carrier Protein S-Malonyltransferase; C494968:fabD protein, E coli; D054889:Fatty Acid Synthase, Type II