Oxidative Stress is Intrinsic to Staphylococcal Adaptation to Fatty Acid Synthesis Antibiotics

Abstract

Antibiotics inhibiting the fatty acid synthesis (FASII) pathway of the major pathogen Staphylococcus aureus reach their enzyme targets, but bacteria continue growth by using environmental fatty acids (eFAs) to produce phospholipids. We assessed how extreme changes in membrane phospholipids provoked by FASII-antibiotics affect global S. aureus physiology. Anti-FASII provoked massive lasting expression changes without genomic rearrangements. Several regulators, rather than one master switch, contributed to the timing of anti-FASII adaptation. Numerous virulence and adhesion factors showed decreased levels and/or activity. Conversely, stress response protein levels increased, and correlated with greater tolerance to peroxides. Notably, peroxide priming stimulated eFA incorporation efficiency and facilitated adaptation to FASII inhibition. These findings establish a link between oxidative stress and FA incorporation. Consistent with major shift in protein expression, anti-FASII-adapted S. aureus killed an insect host more slowly but continued multiplying. Thus, while anti-FASII-adapted populations are less equipped to damage the host, they may be better fit for long term survival, and could constitute a reservoir for re-infection.