Linear Antimicrobial Peptide, Containing a Diindolyl Methane Unnatural Amino Acid, Potentiates Gentamicin Against Methicillin-Resistant Staphylococcus aureus

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2025-03-02 DOI:10.1002/ddr.70070

Shalini Singh, Grace Kaul, Manjulika Shukla, Abdul Akhir, Shubhandra Tripathi, Abhinav Gupta, Rakhi Bormon, Nisanth N. Nair, Sidharth Chopra, Sandeep Verma

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引用次数: 0

Abstract

The headway for the management of emerging resistant microbial strains has become a demanding task. Over the years, antimicrobial peptides (AMP), have been recognized and explored for their highly systematized SAR and antibacterial properties. With this background, we have reported a new class of AMPs. These peptides incorporate an unnatural amino acid, with a motivation from cruciferous bioactive phytochemical bisindoles methane derivatives with highly selective antimicrobial action. These peptides may also be considered as linear derivatives of hirsutide isolated from entomopathogenic fungus. The synthesized peptides were tested for their antimicrobial activity against an ESKAPE pathogen panel, where peptide 3 exhibited equipotent MIC and potent synergistic action along with gentamicin against Staphylococcus aureus and Enterococcus clinical isolates. This combination was also able to repotentiate gentamicin against NRS119, a gentamicin-resistant MRSA. Molecular dynamics study and free energy calculations provided insights to membrane disruptive properties of AMP action, which assisted gentamicin pass through the lipid–water interface.

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线性抗菌肽，含有二吲哚基甲烷非天然氨基酸，增强庆大霉素对抗耐甲氧西林金黄色葡萄球菌

管理新出现的耐药微生物菌株已成为一项艰巨的任务。多年来，抗菌肽（antimicrobial peptides， AMP）因其高度系统化的SAR和抗菌特性而被人们认识和探索。在此背景下，我们报道了一类新的amp。这些肽含有一种非天然氨基酸，其动力来自十字花科生物活性植物化学双吲哚甲烷衍生物，具有高度选择性的抗菌作用。这些多肽也可以被认为是从昆虫病原真菌中分离出来的多毛肽的线性衍生物。合成的肽对ESKAPE病原菌进行了抗菌活性测试，其中肽3与庆大霉素对金黄色葡萄球菌和肠球菌临床分离株表现出等效MIC和强效协同作用。这种组合也能够重新增强庆大霉素对NRS119（一种耐庆大霉素的MRSA）的作用。分子动力学研究和自由能计算提供了AMP作用的膜破坏特性的见解，这有助于庆大霉素通过脂质-水界面。

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

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.