The staphylococcal type VII secretion system impacts daptomycin sensitivity through controlling bacterial cell envelope integrity
The staphylococcal type VII secretion system impacts daptomycin sensitivity through controlling bacterial cell envelope integrity
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VII 型葡萄球菌分泌系统通过控制细菌细胞包膜完整性影响达托霉素敏感性
DOI：
10.1101/2023.11.20.567842
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Smith V
中科院分区：
文献类型：
--
作者：
Smith V
人类病原金黄色葡萄球菌编码一种特殊的VII型分泌系统（T7SS），该系统在细菌感染过程中的毒力中起重要作用。然而，T7SS在感染和细菌生理学中的功能仍不清楚。在这里，我们证明了S。缺乏T7SS效应子EsxC（ΔesxC）的金黄色葡萄球菌菌株对重要的最后手段药物达托霉素以及其他膜靶向抗生素（包括短杆菌肽和双硫堇）高度敏感。为了了解EsxC如何介导抗生素敏感性增加，我们研究了其在葡萄球菌细胞包膜中的功能。扫描电子显微镜分析anesxC突变体揭示了一个独特的细胞表面形态。有趣的是，Δ esxC显示膜流动性降低，改变膜蛋白谱和改变细胞壁合成。该esxC突变体表现出增强的达托霉素结合，这与突变体膜的负电荷增加。钙离子可以结合影响电荷的膜，影响Δ esxC的生长和对达托霉素的敏感性，表明EsxC可能调节钙与膜的结合。此外，在细胞内感染和小鼠皮肤感染模型中，esxC突变体显示出对达托霉素的高度敏感性。因此，我们的数据表明T7 SS效应子EsxC影响S的敏感性。Aureusto膜作用药物，如达托霉素通过调节细胞膜的完整性，表明其作为药物target.Author SummaryT7SS的潜力在细菌中具有一系列的功能，包括细菌生理学中的特定作用，包括DNA摄取，膜的完整性和细菌的发展。金黄色葡萄球菌T7SS在细菌毒力、种内竞争和宿主细胞相互作用中具有重要作用，但其在细菌生理学中的功能尚不清楚。在这里，我们报告了葡萄球菌T7SS效应器EsxC在调节细胞膜和表面完整性中的作用，这会影响膜靶向药物如达托霉素的活性。我们的数据表明，靶向该系统可能会增强现有治疗药物的活性。
The human pathogenStaphylococcus aureusencodes a specialised type VII secretion system (T7SS), which plays an important role in bacterial virulence during infection. However, the functions the T7SS during infection and in bacterial physiology remain unclear. Here we demonstrate thatS. aureusstrains lacking the the T7SS effector EsxC (ΔesxC) was highly sensitive to the important last resort drug, daptomycin, as well as other membrane-targeting antibiotics, including gramicidin and bithionol. To understand how EsxC mediates increased antibiotic sensitivity, we investigated its functions in the staphylococcal cell envelope. Scanning electron microscopy analysis of anesxCmutant revealed a distinct cell surface morphology. Interestingly, ΔesxCdisplayed a decrease in membrane fluidity, altered membrane protein profiles and altered cell wall synthesis. TheesxCmutant demonstrated enhanced daptomycin binding which correlated with the increased negative charge of mutant membranes. Calcium ions, which can bind membranes affecting charge, impacted growth of ΔesxCand sensitivity to daptomycin, suggesting that EsxC may modulate calcium binding to membranes. Furthermore, theesxCmutant displayed a heightened susceptibility to daptomycin during intracellular infection, and in a murine skin infection model. Thus, our data show that the T7SS effector EsxC impacts sensitivity ofS. aureusto membrane-acting drugs such as daptomycin through modulation of cell membrane integrity, indicating its potential as a drug target.Author SummaryT7SS has a range of functions in bacteria including specific roles in bacterial physiology including DNA uptake, membrane integrity and bacterial development. InS. aureusT7SS has been shown to be critical for bacterial virulence, intra-species competition and in host cell interactions, although their functions in bacterial physiology are not clear. Here we report a role of the staphylococcal T7SS effector EsxC in the modulation of the cell membrane and surface integrity, which impacts the activity of membrane targeting drugs like daptomycin. Our data indicate that targeting this system could potentially enhance activity of existing therapeutic agents.