Wang Haibo, Wang Minji, Xu Xiaohan, Gao Peng, Xu Zeling, Zhang Qi, Li Hongyan, Yan Aixin, Kao Richard Yi-Tsun, Sun Hongzhe
Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong S.A.R., People's Republic of China.
School of Biological Sciences, The University of Hong Kong, Hong Kong S.A.R., People's Republic of China.
Nat Commun. 2021 Jun 7;12(1):3331. doi: 10.1038/s41467-021-23659-y.
The rapid emergence of drug resistant Staphylococcus aureus (S. aureus) poses a serious threat to public health globally. Silver (Ag)-based antimicrobials are promising to combat antibiotic resistant S. aureus, yet their molecular targets are largely elusive. Herein, we separate and identify 38 authentic Ag-binding proteins in S. aureus at the whole-cell scale. We then capture the molecular snapshot on the dynamic action of Ag against S. aureus and further validate that Ag could inhibit a key target 6-phosphogluconate dehydrogenase through binding to catalytic His185 by X-ray crystallography. Significantly, the multi-target mode of action of Ag (and nanosilver) endows its sustainable antimicrobial efficacy, leading to enhanced efficacy of conventional antibiotics and resensitization of MRSA to antibiotics. Our study resolves the long-standing question of the molecular targets of silver in S. aureus and offers insights into the sustainable bacterial susceptibility of silver, providing a potential approach for combating antimicrobial resistance.
耐药性金黄色葡萄球菌（S. aureus）的迅速出现对全球公共卫生构成了严重威胁。基于银（Ag）的抗菌剂有望对抗耐抗生素的金黄色葡萄球菌，但其分子靶点在很大程度上仍不清楚。在此，我们在全细胞水平上分离并鉴定了金黄色葡萄球菌中38种真实的Ag结合蛋白。然后，我们捕捉了Ag对金黄色葡萄球菌动态作用的分子瞬间，并通过X射线晶体学进一步验证了Ag可以通过与催化性His185结合来抑制关键靶点6-磷酸葡萄糖酸脱氢酶。值得注意的是，Ag（和纳米银）的多靶点作用模式赋予了其可持续的抗菌效果，从而提高了传统抗生素的疗效，并使耐甲氧西林金黄色葡萄球菌（MRSA）对抗生素重新敏感。我们的研究解决了长期以来关于银在金黄色葡萄球菌中的分子靶点的问题，并为银的可持续细菌敏感性提供了见解，为对抗抗菌药物耐药性提供了一种潜在方法。
