Synergistic activity of menadione in combination with colistin against colistin-susceptible and colistin-resistant Gram-negative bacteria

IF 4.9 2区医学 Q1 INFECTIOUS DISEASES

International Journal of Antimicrobial Agents Pub Date : 2025-04-21 DOI:10.1016/j.ijantimicag.2025.107523

Jun Yang , Huiying Yue , Weifeng Wang , Caiying Lin , Chenchen Li , Jiakuo Chen , Jian-Hua Liu , Yi-Yun Liu

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引用次数: 0

Abstract

Objective

Antibiotic resistance poses a formidable challenge, especially with the emergence of multidrug-resistant Gram-negative bacteria. Colistin serves as a last-resort antibiotic to combat multidrug-resistance, but it is limited by its nephrotoxicity and rising resistance. This study introduces menadione, a synthetic form of vitamin K, as a potential adjuvant to enhance colistin's efficacy against both susceptible and resistant strains of Gram-negative bacteria.

Methods

Through checkerboard dilution assays, we demonstrate that menadione significantly lowers the MICs of colistin, with fractional inhibitory concentration indices ranging from 0.031 to 0.375. Furthermore, synergistic effects were confirmed via time–kill kinetics, indicating effective bacterial growth inhibition. The study also explores the mechanism underlying this synergy, revealing that menadione in combination with colistin disrupts the bacterial outer membrane, reduces the proton motive force and adenosine triphosphate content, and amplify the production of reactive oxygen species, contributing to bacterial cell death.

Results

Menadione was shown to prevent the evolution of colistin resistance.

Conclusions

This research highlights the potential of using menadione as a colistin adjuvant to combat antibiotic-resistant Gram-negative bacteria, providing a promising approach to extend the utility of existing antibiotics in clinical settings.

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美萘醌联合粘菌素对粘菌素敏感和耐粘菌素革兰氏阴性菌的协同作用。

抗生素耐药性是一项艰巨的挑战，特别是随着多重耐药（MDR）革兰氏阴性细菌的出现。粘菌素是对抗耐多药耐药性的最后手段，但由于其肾毒性和不断上升的耐药性，它受到限制。本研究介绍了维生素K的合成形式美萘醌，作为一种潜在的佐剂，以增强粘菌素对革兰氏阴性菌敏感和耐药菌株的疗效。通过棋盘稀释试验，我们发现美萘醌显著降低了黏菌素的最低抑制浓度（mic），其FICI范围为0.031至0.375。此外，通过时间杀伤动力学证实了协同效应，表明有效的细菌生长抑制。该研究还探讨了这种协同作用的机制，揭示了美萘醌与粘菌素联合破坏细菌外膜，降低质子动力（PMF）和ATP含量，并增加活性氧（ROS）的产生，导致细菌细胞死亡。此外，menadione被证明可以防止粘菌素耐药性的演变。这项研究强调了使用美萘醌作为粘菌素佐剂来对抗抗生素耐药的革兰氏阴性菌的潜力，为扩大现有抗生素在临床环境中的效用提供了一种有希望的方法。

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

International Journal of Antimicrobial Agents 医学-传染病学

CiteScore

21.60

自引率

0.90%

发文量

176

审稿时长

36 days

期刊介绍： The International Journal of Antimicrobial Agents is a peer-reviewed publication offering comprehensive and current reference information on the physical, pharmacological, in vitro, and clinical properties of individual antimicrobial agents, covering antiviral, antiparasitic, antibacterial, and antifungal agents. The journal not only communicates new trends and developments through authoritative review articles but also addresses the critical issue of antimicrobial resistance, both in hospital and community settings. Published content includes solicited reviews by leading experts and high-quality original research papers in the specified fields.