Tetracyclines at subinhibitory concentrations are lethal for NADH peroxidase-deficient mutants of Enterococcus faecium.

IF 3.9 2区医学 Q1 INFECTIOUS DISEASES

Journal of Antimicrobial Chemotherapy Pub Date : 2025-06-03 DOI:10.1093/jac/dkaf105

Valentin Wasselin, Aurélie Budin-Verneuil, Isabelle Rincé, Florie Desriac, Julie Plouhinec, Amine M Boukerb, Axel Hartke, Abdellah Benachour, Eliette Riboulet-Bisson

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引用次数: 0

Abstract

Objectives: Tigecycline is a bacteriostatic antibiotic member of the glycylcycline family that inhibits protein synthesis. Tigecycline is a last-line treatment for infections caused by MDR pathogens like vancomycin-resistant Enterococcus faecium (VR-Efm). We recently explored oxidative stress defences in E. faecium and we here aimed to assess their role in antibiotic resistance.

Methods: Antibiotic susceptibility was evaluated in mutants deficient in primary oxidative stress defences by monitoring bacterial survival after a 24 h treatment. Hydrogen peroxide (H2O2) levels were quantified to link bacterial survival to oxidative stress.

Results: Unexpectedly, tigecycline and other tetracyclines were lethal for VR-Efm AUS0004 mutants deficient in NADH peroxidase (Npr) at concentrations below their MICs. Lethality seemed to correlate with increased H2O2 accumulation in the Δnpr mutant. H2O2 production in Efm AUS0004 was mainly mediated by lactate oxidase Lox1, whereas Lox2 and pyruvate oxidase (Pox) had minor or no roles. Tigecycline was not lethal for a ΔnprΔlox1 double mutant, suggesting lethality results from both antibiotic effect and peroxide accumulation.

Conclusions: This study might pave the way to develop strategies aimed at potentiating tigecycline action by increasing endogenous H2O2 production and/or impairing H2O2 detoxification, potentially improving treatment efficiencies for VR-Efm infections with this last-line antibiotic.

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在亚抑制浓度四环素是致命的NADH过氧化物酶缺陷的屎肠球菌突变体。

目的：替加环素是抑制蛋白质合成的甘环素家族的抑菌抗生素成员。替加环素是耐万古霉素屎肠球菌等耐多药病原体引起的感染的最后一线治疗方法。我们最近探索了粪肠杆菌的氧化应激防御，我们在这里的目的是评估它们在抗生素耐药性中的作用。方法：通过监测处理24小时后细菌存活情况，评估原发性氧化应激防御缺陷突变体的抗生素敏感性。过氧化氢（H2O2）水平被量化，将细菌存活与氧化应激联系起来。结果：出乎意料的是，替加环素和其他四环素对NADH过氧化物酶（Npr）缺乏的VR-Efm AUS0004突变体在低于其mic的浓度下是致命的。致死率似乎与Δnpr突变体中H2O2积累的增加有关。Efm AUS0004的H2O2生成主要由乳酸氧化酶Lox1介导，而Lox2和丙酮酸氧化酶（Pox）则很少或没有作用。替加环素对ΔnprΔlox1双突变体不致命，表明致死率来自抗生素作用和过氧化物积累。结论：该研究可能为开发通过增加内源性H2O2生成和/或破坏H2O2解毒来增强替加环素作用的策略铺平道路，从而有可能提高使用这种最后一线抗生素治疗VR-Efm感染的效率。

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

Journal of Antimicrobial Chemotherapy 医学-传染病学

CiteScore

9.20

自引率

5.80%

发文量

423

审稿时长

2-4 weeks

期刊介绍： The Journal publishes articles that further knowledge and advance the science and application of antimicrobial chemotherapy with antibiotics and antifungal, antiviral and antiprotozoal agents. The Journal publishes primarily in human medicine, and articles in veterinary medicine likely to have an impact on global health.