Permissive Fatty Acid Incorporation Promotes Staphylococcal Adaptation to FASII Antibiotics in Host Environments
Gérald Kénanian,
Claire Morvan,
Antonin Weckel,
Amit Pathania,
Jamila Anba-Mondoloni,
David Halpern,
Marine Gaillard,
Audrey Solgadi,
Laetitia Dupont,
Céline Henry,
Claire Poyart,
Agnès Fouet,
Gilles Lamberet,
Karine Gloux,
Alexandra Gruss
Affiliations
Gérald Kénanian
Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France
Claire Morvan
Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France
Antonin Weckel
Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, 75014 Paris, France
Amit Pathania
Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France
Jamila Anba-Mondoloni
Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France
David Halpern
Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France
Marine Gaillard
Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, 75014 Paris, France
Audrey Solgadi
SAMM, UMS IPSIT, Faculté de Pharmacie, Université Paris-Saclay, Chatenay-Malabry, France
Laetitia Dupont
Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France
Céline Henry
PAPPSO Platform, Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
Claire Poyart
Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, 75014 Paris, France; Centre National de Référence des Streptocoques, Hôpitaux Universitaires Paris Centre Site Cochin, APHP, Paris, France
Agnès Fouet
Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, 75014 Paris, France
Gilles Lamberet
Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France
Karine Gloux
Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France
Alexandra Gruss
Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France; Corresponding author
Summary: The essentiality of fatty acid synthesis (FASII) products in the human pathogen Staphylococcus aureus is the underlying rationale for FASII-targeted antimicrobial drug design. Reports of anti-FASII efficacy in animals support this choice. However, restricted test conditions used previously led us to investigate this postulate in a broader, host-relevant context. We report that S. aureus rapidly adapts to FASII antibiotics without FASII mutations when exposed to host environments. FASII antibiotic administration upon signs of infection, rather than just after inoculation as commonly practiced, fails to eliminate S. aureus in a septicemia model. In vitro, serum lowers S. aureus membrane stress, leading to a greater retention of the substrates required for environmental fatty acid (eFA) utilization: eFAs and the acyl carrier protein. In this condition, eFA occupies both phospholipid positions, regardless of anti-FASII selection. Our results identify S. aureus membrane plasticity in host environments as a main limitation for using FASII antibiotics in monotherapeutic treatments. : FASII antibiotics are emerging as potential alternative therapeutics with the rise of antibiotic resistance; however, their efficacy has been controversial. Kénanian et al. find host fatty acids can compensate MRSA inhibition, thwarting the efficacy of FASII inhibitors. Bacteria can scavenge and incorporate exogenous (host) fatty acids to enable anti-FASII adaptation. Keywords: firmicute pathogens, infection, treatment failure, conditional antibiotic adaptation, antibiotic resistance, membrane phospholipids, fatty acid stress, triclosan, AFN-1252