Human serum triggers antibiotic tolerance in Staphylococcus aureus.
Human serum triggers antibiotic tolerance in Staphylococcus aureus.
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DOI：
10.1038/s41467-022-29717-3
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发表时间：
2022-04-19
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
金黄色葡萄球菌经常引起难以治疗的感染，导致高比例的持续性和复发性感染。在这里，为了了解宿主环境如何影响治疗结果，我们研究了人血清对葡萄球菌抗生素敏感性的影响。我们发现，血清引发了高度的耐受性脂肽抗生素达托霉素和其他几类抗生素。血清诱导的达托霉素耐受是由于两个独立的机制。首先，宿主防御肽LL-37通过触发葡萄球菌GraRS双组分系统诱导耐受性，导致肽聚糖积累增加。其次，完全耐受需要膜心磷脂丰度的GraRS非依赖性增加。当两种机制都被阻断时，S.在血清中孵育的金黄色葡萄球菌与在实验室培养基中生长的金黄色葡萄球菌一样对达托霉素敏感。我们的工作表明，宿主因素可以通过不同的机制显着调节抗生素敏感性，联合治疗可能提供一种减轻这种情况的方法。宿主环境可能通过不明确的机制影响抗菌治疗的结果。在这里，Ledger等人表明，人血清通过诱导导致细菌膜和细胞壁组成变化的特定途径降低抗生素达托霉素对金黄色葡萄球菌的效力。
Staphylococcus aureus frequently causes infections that are challenging to treat, leading to high rates of persistent and relapsing infection. Here, to understand how the host environment influences treatment outcomes, we study the impact of human serum on staphylococcal antibiotic susceptibility. We show that serum triggers a high degree of tolerance to the lipopeptide antibiotic daptomycin and several other classes of antibiotic. Serum-induced daptomycin tolerance is due to two independent mechanisms. Firstly, the host defence peptide LL-37 induces tolerance by triggering the staphylococcal GraRS two-component system, leading to increased peptidoglycan accumulation. Secondly, GraRS-independent increases in membrane cardiolipin abundance are required for full tolerance. When both mechanisms are blocked, S. aureus incubated in serum is as susceptible to daptomycin as when grown in laboratory media. Our work demonstrates that host factors can significantly modulate antibiotic susceptibility via diverse mechanisms, and combination therapy may provide a way to mitigate this. The host environment can impact the outcomes of antimicrobial therapies through unclear mechanisms. Here, Ledger et al. show that human serum reduces the efficacy of the antibiotic daptomycin against Staphylococcus aureus by inducing specific pathways leading to changes in the composition of the bacterial membrane and cell wall.
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