文献类型：期刊文献

英文题名：Enhancing the antibacterial efficacy of vancomycin analogues: targeting metallo-β-lactamases and cell wall biosynthesis

作者：Sarkar, Paramita[1];Xu, Weipan[2];Vazquez-Hernandez, Melissa[3];Dhanda, Geetika[1];Tripathi, Shubhandra[4];Basak, Debajyoti[1];Xie, Hexin[2];Schipp, Lea[3];Dietze, Pascal[3];Bandow, Julia E.[3];Nair, Nishanth N.[4];Haldar, Jayanta[1,5]

机构：[1]Jawaharlal Nehru Ctr Adv Sci Res, New Chem Unit, Antimicrobial Res Lab, Jakkur 560064, Bengaluru, India;[2]East China Univ Sci & Technol, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China;[3]Ruhr Univ Bochum, Fac Biol & Biotechnol, Appl Microbiol, Univ Str 150, D-44780 Bochum, Germany;[4]Indian Inst Technol Kanpur, Dept Chem, Kanpur, India;[5]Jawaharlal Nehru Ctr Adv Sci Res, Sch Adv Mat, Jakkur 560064, Karnataka, India

年份：2024

卷号：15

期号：39

起止页码：16307

外文期刊名：CHEMICAL SCIENCE

收录：;EI(收录号：20244117179457);WOS:【SCI-EXPANDED(收录号:WOS:001314540600001)】；

基金：We acknowledge DST-DAAD bilateral cooperation project (INT/FRG/DAAD/P-15/2018), DST-BRICS mutilateral cooperation project (DST/IMRD/BRICS/PilotCall2/MBLI/2018(G)) and JNCASR for funding. JEB acknowledges funding from the DAAD Program DST 2018 (57389759). We thank Dr Sidharth Chopra (Central Drug Research Institute, Lucknow) and Dr Sulagna Basu (National Institute of Cholera and Enteric Diseases, Kolkata) for the gift of drug-resistant clinical isolates.

语种：英文

外文关键词：Bioactivity - Cell membranes

摘要：Vancomycin is a crucial last-resort antibiotic for tackling Gram-positive bacterial infections. However, its potency fails against the more difficult-to-treat Gram-negative bacteria (GNB). Vancomycin derivatives have shown promise as broad-spectrum antibacterials, but are still underexplored. Toward this, we present a novel strategy wherein we substitute the sugar moiety of vancomycin with a dipicolyl amine group, yielding VanNHdipi. This novel glycopeptide enhances its efficacy against vancomycin-resistant bacteria by up to 100-fold. A comprehensive approach involving microbiological assays, biochemical analyses, proteomics, and computational studies unraveled the impact of this design on biological activity. Our investigations reveal that VanNHdipi, like vancomycin, disrupts membrane-bound steps of cell wall synthesis inducing envelope stress, while also interfering with the structural integrity of the cytoplasmic membrane, setting it apart from vancomycin. Most noteworthy is its potency against critical GNB producing metallo-beta-lactamases (MBLs). VanNHdipi effectively inactivates various MBLs with IC50 in the range of 0.2-10 mu M resulting in resensitization of MBL-producing bacteria to carbapenems. Molecular docking and molecular dynamics (MD) studies indicate that H-bonding interactions between the sugar moiety of the vancomycin derivative with the amino acids on the surface of NDM-1 facilitate enhanced binding affinity for the enzyme. This work expands the scope of vancomycin derivatives and offers a promising new avenue for combating antibiotic resistance. A two-in-one vancomycin derivative that acts through multiple mechanisms to inhibit drug-resistant Gram-positive bacteria and resensitizes critical priority Gram-negative pathogens to carbapenems.