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

Abstract

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