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

Essentiality of fatty acid synthesis (FASII) products in 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 (AFN-1252 and triclosan) when exposed to host environments. DNA sequencing of FASII-adapted strains shows that adaptation occurs without FASII mutations. One isolate displayed no detectable genome mutations. The other clones carried SNPs corresponding to commonly found variants, and are likely unrelated to FASII antibiotic adaptation. The absence of FASII mutations distinguishes this adaptation mechanism from resistance due to FASII target or initiator gene mutations. S. aureus evasion of FASII antibiotics in serum identifies a novel strategy of condition-dependent adaptation.