Repurposing TAK-285 as An Antibacterial Agent against Multidrug-Resistant Staphylococcus aureus by Targeting Cell Membrane.

IF 2.3 3区 生物学 Q3 MICROBIOLOGY
Jinlian Huang, Zhichao Xu, Peikun He, Zhiwei Lin, Renhai Peng, Zhijian Yu, Peiyu Li, Qiwen Deng, Xiaoju Liu
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Abstract

Infections and antimicrobial resistance are becoming serious global public health crises. Multidrug-resistant Staphylococcus aureus (S. aureus) infections necessitate novel antimicrobial development. In this study, we demonstrated TAK-285, a novel dual HER2/EGFR inhibitor, exerted antibacterial activity against 17 clinical methicillin-resistant S. aureus (MRSA) and 15 methicillin sensitive S. aureus (MSSA) isolates in vitro, with a minimum inhibitory concentration (MIC) of 13.7 μg/mL. At 1 × MIC, TAK-285 completely inhibited the growth of S. aureus bacterial planktonic cells, and at 2 × MIC, it exhibited a superior inhibitory effect on intracellular S. aureus SA113-GFP compared to linezolid. Moreover, TAK-285 effectively inhibited biofilm formation at sub-MIC, eradicated mature biofilm and eliminated bacteria within biofilms, as confirmed by CLSM. Furthermore, the disruption of cell membrane permeability and potential was found by TAK-285 on S. aureus, suggesting its targeting of cell membrane integrity. Global proteomic analysis demonstrated that TAK-285 disturbed the metabolic processes of S. aureus, interfered with biofilm-related gene expression, and disrupted membrane-associated proteins. Conclusively, we repurposed TAK-285 as an antimicrobial with anti-biofilm properties against S. aureus by targeting cell membrane. This study provided strong evidence for the potential of TAK-285 as a promising antimicrobial agent against S. aureus.

通过靶向细胞膜将 TAK-285 重新用作抗耐多药金黄色葡萄球菌的抗菌剂
感染和抗菌药耐药性正在成为严重的全球公共卫生危机。耐多药金黄色葡萄球菌(S. aureus)感染需要新型抗菌药的开发。在这项研究中,我们证明了新型 HER2/EGFR 双抑制剂 TAK-285 在体外对 17 种临床耐甲氧西林金黄色葡萄球菌(MRSA)和 15 种甲氧西林敏感金黄色葡萄球菌(MSSA)分离株具有抗菌活性,最低抑菌浓度(MIC)为 13.7 μg/mL。在 1 倍 MIC 时,TAK-285 可完全抑制金黄色葡萄球菌浮游细胞的生长;在 2 倍 MIC 时,它对细胞内金黄色葡萄球菌 SA113-GFP 的抑制效果优于利奈唑胺。此外,经 CLSM 证实,TAK-285 能在亚 MIC 浓度下有效抑制生物膜的形成,根除成熟的生物膜,并消灭生物膜内的细菌。此外,TAK-285 还能破坏金黄色葡萄球菌细胞膜的通透性和电位,这表明它以细胞膜完整性为靶点。全局蛋白质组分析表明,TAK-285干扰了金黄色葡萄球菌的代谢过程,干扰了生物膜相关基因的表达,并破坏了膜相关蛋白。最终,我们将TAK-285作为一种抗菌剂,通过靶向细胞膜来对抗金黄色葡萄球菌的生物膜特性。这项研究有力地证明了 TAK-285 作为金黄色葡萄球菌抗菌剂的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Current Microbiology
Current Microbiology 生物-微生物学
CiteScore
4.80
自引率
3.80%
发文量
380
审稿时长
2.5 months
期刊介绍: Current Microbiology is a well-established journal that publishes articles in all aspects of microbial cells and the interactions between the microorganisms, their hosts and the environment. Current Microbiology publishes original research articles, short communications, reviews and letters to the editor, spanning the following areas: physiology, biochemistry, genetics, genomics, biotechnology, ecology, evolution, morphology, taxonomy, diagnostic methods, medical and clinical microbiology and immunology as applied to microorganisms.
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