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Inverse correlation between stress response and virulence factor expression in FASII antibiotic-adapted Staphylococcus aureus and consequences for infection

ABSTRACT: Proving functionality in the host environment is a crucial step in antimicrobial development pipelines. Antibiotics targeting fatty acid synthesis (FASII) of the major pathogen Staphylococcus aureus actively inhibit FASII but do not prevent in vivo growth, as bacteria compensate the FASII block by using environmental fatty acids. We used proteomics and phosphoproteomics to elucidate S. aureus responses to anti-FASII in host-relevant conditions. S. aureus responded to anti-FASII treatment in serum by massive reprogramming, including overall increases in stress response proteins, and decreases in virulence factors. Adaptation is accelerated by pretreatment with hydrogen peroxide. These findings suggested that anti-FASII adapted cells might be better prepared for survival and less equipped to damage the host. Infection by anti-FASII-adapted versus non-treated S. aureus was challenged in the Galleria mellonella model. Time to mortality was longer in insects infected by anti-FASII-treated bacteria compared to those infected by non-treated S. aureus. However, bacterial counts in infected dead insects were comparable for both groups. These results support the hypothesis that higher stress response and lower virulence factor expression, as shown here in FASII-antibiotic-adapted bacteria, may prepare S. aureus for chronic infection.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Staphylococcus Aureus (ncbitaxon:1280)

SUBMITTER: Alexandra Gruss

PROVIDER: MSV000089781 | MassIVE | Fri Jul 01 03:20:00 BST 2022

REPOSITORIES: MassIVE

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FASII antibiotic adaptation reprograms Staphylococcus aureus behavior

Project description:Proving functionality in the host environment is a crucial step in antimicrobial development pipelines. Antibiotics targeting fatty acid synthesis (FASII) of the major pathogen Staphylococcus aureus actively inhibit FASII but do not prevent in vivo growth, as bacteria compensate the FASII block by using environmental fatty acids. We used proteomics and phosphoproteomics to elucidate S. aureus responses to anti-FASII in host-relevant conditions. S. aureus responded to anti-FASII treatment in serum by massive reprogramming. A striking inverse correlation was observed in anti-FASII-adapted S. aureus, between amounts of stress response proteins that increase, and virulence factors that decrease. These findings suggest that anti-FASII adapted cells might be better prepared for survival and less equipped to damage the host. Infection by anti-FASII-adapted versus non-treated S. aureus was challenged in the Galleria mellonella model. Time to mortality was longer in insects infected by anti-FASII-treated bacteria compared to those infected by non-treated S. aureus. However, bacterial counts in infected dead insects were comparable for both groups. These results support the hypothesis that higher stress response and lower virulence factor expression, as shown here in FASII-antibiotic-adapted bacteria, may set the stage for persistent infection

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