The Antimicrobial Activity of the Glycocin Sublancin Is Dependent on an Active Phosphoenolpyruvate-Sugar Phosphotransferase System.
The Antimicrobial Activity of the Glycocin Sublancin Is Dependent on an Active Phosphoenolpyruvate-Sugar Phosphotransferase System.
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DOI：
10.1021/acsinfecdis.1c00157
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发表时间：
2021-08-13
影响因子：
5.3
通讯作者：
van der Donk WA
中科院分区：
文献类型：
--
作者：
Biswas S;Wu C;van der Donk WA
抗生素耐药性是一个全球性挑战，由于可用靶点数量有限而更加复杂。糖肽是一种抗微生物的糖肽，被认为具有新的靶点。先前的研究表明，糖蛋白亚蓝蛋白168的作用机制涉及葡萄糖摄取系统。磷酸烯醇丙酮酸：糖磷酸转移酶系统（PTS）在输入过程中磷酸化葡萄糖上的C6羟基。由于sublancin在暴露的环上的Cys上携带葡萄糖，我们研究了这种葡萄糖的磷酸化是否可能参与其作用机制，通过用木糖替代。令人惊讶的是，木糖类似物比野生型sublancin更有活性，并且仍然需要葡萄糖PTS才有活性。过表达的PTS的个别组件呈现细胞更敏感的sublancin和他们的电阻频率大大降低。这些观察结果表明，sublancin以某种形式被葡萄糖PTS激活，或者sublancin赋予PTS有害的功能获得。超分辨率显微镜研究与荧光sublancin和荧光标记的PTS蛋白质显示本地化的两极细胞。在将PTS突变最小化的条件下产生的抗性突变体揭示了FliQ中的突变，FliQ是参与鞭毛蛋白输出过程的蛋白质。FliQ的过表达导致细胞对亚蓝蛋白的敏感性降低。总的来说，这些研究结果强制执行一个模型，其中PTS是所需的sublancin活动，无论是通过诱导有害的功能获得或通过激活或运输sublancin。
Antimicrobial resistance is a global challenge that is compounded by the limited number of available targets. Glycocins are antimicrobial glycopeptides that are believed to have novel targets. Previous studies have shown that the mechanism of action of the glycocin sublancin 168 involves the glucose uptake system. The phosphoenolpyruvate:sugar phosphotransferase system (PTS) phosphorylates the C6 hydroxyl group on glucose during import. Since sublancin carries a glucose on a Cys on an exposed loop, we investigated whether phosphorylation of this glucose might be involved in its mechanism of action by replacement with xylose. Surprisingly, the xylose analog was more active than wild-type sublancin and still required the glucose PTS for activity. Overexpression of the individual components of the PTS rendered cells more sensitive to sublancin and their resistance frequency was considerably decreased. These observations suggest that sublancin is activated in some form by the glucose PTS or that sublancin imparts a deleterious gain-of-function on the PTS. Superresolution microscopy studies with fluorescent sublancin and fluorescently labeled PTS proteins revealed localization of both at the poles of cells. Resistance mutants raised under conditions that would minimize mutation of the PTS revealed mutations in FliQ, a protein involved in the flagellar protein export process. Overexpression of FliQ lead to decreased sensitivity of cells to sublancin. Collectively, these findings enforce a model in which the PTS is required for sublancin activity, either by inducing a deleterious gain-of-function or by activating or transporting sublancin.
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