FASII antibiotic adaptation reprograms Staphylococcus aureus behavior

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

在宿主环境中验证抗菌活性是抗菌药物开发流程中的关键环节。靶向主要致病菌金黄色葡萄球菌（Staphylococcus aureus）脂肪酸合成II型（FASII）的抗生素，虽可有效抑制FASII活性，却无法阻止细菌在体内的生长——这是因为细菌可通过摄取环境中的脂肪酸弥补FASII通路被阻断的缺陷。本研究借助蛋白质组学与磷酸化蛋白质组学技术，阐明了金黄色葡萄球菌在宿主相关培养条件下对抗FASII疗法的应答机制。金黄色葡萄球菌在血清环境中经抗FASII处理后，发生了大规模的基因表达重编程。在经抗FASII适应的金黄色葡萄球菌中，研究人员观察到了显著的负相关关系：应激反应蛋白的表达量随之上调，而毒力因子的表达量则显著下调。上述结果表明，经抗FASII适应的细菌或更利于存活，但对宿主的致病能力有所减弱。本研究利用大蜡螟（Galleria mellonella）感染模型，对比了经抗FASII适应与未处理的金黄色葡萄球菌的致病能力。与感染未处理细菌的大蜡螟相比，感染经抗FASII处理细菌的大蜡螟的死亡时间显著延长。但两组感染死亡大蜡螟体内的细菌载量并无显著差异。上述结果验证了如下假说：正如本研究中FASII抗生素适应株所表现的那样，更高的应激反应水平与更低的毒力因子表达，可能为持续性感染的发生奠定基础。