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

Abstract

Development of fatty acid synthesis pathway (FASII) inhibitors against the major human pathogen Staphylococcus aureus hinges on the accepted but unproven postulate that an endogenously synthesized branched chain fatty acid is required to complete membrane phospholipids. Evidence for anti-FASII efficacy in animal models supported this view. However, restricted test conditions used previously to show FASII antibiotic efficacy led us to investigate these questions in a broader, host-relevant context. We report that S. aureus rapidly adapts to FASII antibiotics without FASII mutations when exposed to host environments. Treatment with a lead FASII antibiotic upon signs of infection, rather than just after inoculation as commonly practiced, failed to eliminate S. aureus from infected organs in a septicemia model. In vitro, addition of serum facilitated rapid S. aureus FASII bypass by environmental fatty acid (eFA) replacement in phospholipids. Serum lowers membrane stress, leading to increased retention of the two substrates required for exogenous fatty acid (eFA) utilization. In these conditions, eFA occupy both phospholipid positions 1 and 2, regardless of anti-FASII selection. This study revises conclusions on S. aureus fatty acid requirements by disproving the postulate of fatty acid stringency, and reveals an Achilles heel for using FASII antibiotics to treat infection in monotherapy.\n\nSignificance statementAntibiotic discovery to overcome treatment failure has huge socio-medical and economic stakes. The fatty acid synthesis (FASII) pathway is considered an ideal druggable target against the human pathogen Staphylococcus aureus, based on evidence of anti-FASII efficacy in infection models, and the postulate that S. aureus synthesizes an irreplaceable fatty acid. We report that S. aureus alters its behavior in host-relevant conditions. Administering FASII antibiotics upon signs of infection, rather than just after inoculation as frequently practiced, failed to clear septicemic infections. In serum, S. aureus rapidly overcomes FASII antibiotics by incorporating alternative fatty acids. We conclude that previously, premature antibiotic treatments and experimental constraints masked S. aureus antibiotic adaptation capacity. These findings should help streamline future drug development programs.