AMXT-1501 targets membrane phospholipids against Gram-positive and -negative multidrug-resistant bacteria.

IF 8.4 2区医学 Q1 IMMUNOLOGY Emerging Microbes & Infections Pub Date : 2024-12-01 Epub Date: 2024-02-29 DOI:10.1080/22221751.2024.2321981

Jinxin Zheng, Xiaoju Liu, Yanpeng Xiong, Qingyin Meng, Peiyu Li, Fan Zhang, Xiaoming Liu, Zhiwei Lin, Qiwen Deng, Zewen Wen, Zhijian Yu

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Abstract

The rapid proliferation of multidrug-resistant (MDR) bacterial pathogens poses a serious threat to healthcare worldwide. Carbapenem-resistant (CR) Enterobacteriaceae, which have near-universal resistance to available antimicrobials, represent a particularly concerning issue. Herein, we report the identification of AMXT-1501, a polyamine transport system inhibitor with antibacterial activity against Gram-positive and -negative MDR bacteria. We observed minimum inhibitory concentration (MIC)₅₀/MIC₉₀ values for AMXT-1501 in the range of 3.13-12.5 μM (2.24-8.93 μg /mL), including for methicillin-resistant Staphylococcus aureus (MRSA), CR Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. AMXT-1501 was more effective against MRSA and CR E. coli than vancomycin and tigecycline, respectively. Subinhibitory concentrations of AMXT-1501 reduced the biofilm formation of S. aureus and Enterococcus faecalis. Mechanistically, AMXT-1501 exposure damaged microbial membranes and increased membrane permeability and membrane potential by binding to cardiolipin (CL) and phosphatidylglycerol (PG). Importantly, AMXT-1501 pressure did not induce resistance readily in the tested pathogens.

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AMXT-1501 以膜磷脂为靶标，可对抗革兰氏阳性和阴性多重耐药菌。

耐多药（MDR）细菌病原体的迅速扩散对全球医疗保健构成了严重威胁。耐碳青霉烯类（CR）肠杆菌科细菌对现有抗菌药物几乎具有普遍耐药性，是一个特别令人担忧的问题。在此，我们报告了对革兰氏阳性和阴性 MDR 细菌具有抗菌活性的多胺转运系统抑制剂 AMXT-1501的鉴定结果。我们观察到 AMXT-1501 的最小抑菌浓度 (MIC)50/MIC90 值范围为 3.13-12.5 μM（2.24-8.93 μg /mL），包括耐甲氧西林金黄色葡萄球菌（MRSA）、CR 大肠埃希菌、肺炎克雷伯菌和铜绿假单胞菌。与万古霉素和替加环素相比，AMXT-1501 对 MRSA 和 CR 大肠杆菌分别更有效。亚抑制浓度的 AMXT-1501 可减少金黄色葡萄球菌和粪肠球菌生物膜的形成。从机理上讲，AMXT-1501 暴露会破坏微生物膜，并通过与心磷脂（CL）和磷脂酰甘油（PG）结合而增加膜渗透性和膜电位。重要的是，AMXT-1501 的压力不会轻易诱导受试病原体产生抗药性。

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

Emerging Microbes & Infections IMMUNOLOGY-MICROBIOLOGY

CiteScore

26.20

自引率

2.30%

发文量

276

审稿时长

20 weeks

期刊介绍： Emerging Microbes & Infections is a peer-reviewed, open-access journal dedicated to publishing research at the intersection of emerging immunology and microbiology viruses. The journal's mission is to share information on microbes and infections, particularly those gaining significance in both biological and clinical realms due to increased pathogenic frequency. Emerging Microbes & Infections is committed to bridging the scientific gap between developed and developing countries. This journal addresses topics of critical biological and clinical importance, including but not limited to: - Epidemic surveillance - Clinical manifestations - Diagnosis and management - Cellular and molecular pathogenesis - Innate and acquired immune responses between emerging microbes and their hosts - Drug discovery - Vaccine development research Emerging Microbes & Infections invites submissions of original research articles, review articles, letters, and commentaries, fostering a platform for the dissemination of impactful research in the field.