2. Academic Validation
  3. Permissive Fatty Acid Incorporation Promotes Staphylococcal Adaptation to FASII Antibiotics in Host Environments

Permissive Fatty Acid Incorporation Promotes Staphylococcal Adaptation to FASII Antibiotics in Host Environments

  • Cell Rep. 2019 Dec 17;29(12):3974-3982.e4. doi: 10.1016/j.celrep.2019.11.071.
Gérald Kénanian 1,  Claire Morvan 1,  Antonin Weckel 2,  Amit Pathania 1,  Jamila Anba-Mondoloni 1,  David Halpern 1,  Marine Gaillard 2,  Audrey Solgadi 3,  Laetitia Dupont 1,  Céline Henry 4,  Claire Poyart 5,  Agnès Fouet 2,  Gilles Lamberet 1,  Karine Gloux 1,  Alexandra Gruss 6
Affiliations

Affiliations

  • 1 Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France.
  • 2 Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, 75014 Paris, France.
  • 3 SAMM, UMS IPSIT, Faculté de Pharmacie, Université Paris-Saclay, Chatenay-Malabry, France.
  • 4 PAPPSO Platform, Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.
  • 5 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.
  • 6 Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy en Josas, France. Electronic address: alexandra.gruss@inra.fr.
PMID: 31851927 DOI: 10.1016/j.celrep.2019.11.071
Abstract

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.

Keywords

AFN-1252; antibiotic resistance; conditional antibiotic adaptation; fatty acid stress; firmicute pathogens; infection; membrane phospholipids; treatment failure; triclosan.

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