Sarkar Paramita, De Kathakali, Modi Malvika, Dhanda Geetika, Priyadarshini Richa, Bandow Julia E, Haldar Jayanta
Antimicrobial Research Laboratory, New Chemistry Unit and School of Advanced Materials, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) Jakkur Bengaluru 560064 Karnataka India
Department of Life Sciences, School of Natural Sciences, Shiv Nadar University Dadri 201314 UP India.
Chem Sci. 2023 Jan 6;14(9):2386-2398. doi: 10.1039/d2sc05600c. eCollection 2023 Mar 1.
Resistance to vancomycin, a life-saving drug against Gram-positive bacterial infections necessitates developing alternative therapeutics. Herein, we report vancomycin derivatives that assimilate mechanisms beyond d-Ala-d-Ala binding. The role of hydrophobicity towards the structure and function of the membrane-active vancomycin showed that alkyl-cationic substitutions favored broad-spectrum activity. The lead molecule, VanQAmC delocalized the cell division protein MinD in , implying an impact on bacterial cell division. Further examination of wild-type, GFP-FtsZ, or GFP-FtsI producing- and Δ mutants of revealed filamentous phenotypes and delocalization of the FtsI protein. The findings indicate that VanQAmC also inhibits bacterial cell division, a property previously unknown for glycopeptide antibiotics. The conjunction of multiple mechanisms contributes to its superior efficacy against metabolically active and inactive bacteria, wherein vancomycin is ineffective. Additionally, VanQAmC exhibits high efficacy against methicillin-resistant (MRSA) and in mouse models of infection.
对万古霉素产生耐药性，而万古霉素是一种对抗革兰氏阳性菌感染的救命药物，这就需要开发替代疗法。在此，我们报告了一些万古霉素衍生物，它们融合了除与d-Ala-d-Ala结合之外的机制。疏水性对膜活性万古霉素的结构和功能的作用表明，烷基阳离子取代有利于广谱活性。先导分子VanQAmC使细胞分裂蛋白MinD在（此处原文缺失具体位置信息）中发生错位，这意味着对细菌细胞分裂有影响。对野生型、产生绿色荧光蛋白FtsZ或绿色荧光蛋白FtsI的（此处原文缺失具体菌株信息）及其Δ突变体的进一步研究揭示了丝状表型和FtsI蛋白的错位。这些发现表明VanQAmC也抑制细菌细胞分裂，这是糖肽类抗生素以前未知的特性。多种机制的结合有助于其对代谢活跃和不活跃细菌具有卓越的疗效，而万古霉素对这些细菌无效。此外，在感染小鼠模型中，VanQAmC对耐甲氧西林金黄色葡萄球菌（MRSA）和（此处原文缺失具体菌株信息）表现出高效。
