Isoniazid potentiates tigecycline to kill methicillin-resistant Staphylococcus aureus.

IF 8.4 2区 医学 Q1 IMMUNOLOGY
Emerging Microbes & Infections Pub Date : 2025-12-01 Epub Date: 2024-12-09 DOI:10.1080/22221751.2024.2434587
Xuan-Wei Chen, Hao-Qing Chen, Jia-Han Wu, Zhi-Han Wang, Yu-Qing Zhou, Si-Qi Tian, Bo Peng
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引用次数: 0

Abstract

Therapeutic option for treating methicillin-resistant Staphylococcus aureus (MRSA) infection is urgently required since its resistance to a broad spectrum of currently available antibiotics. Here, we report that isoniazid is able to potentiate the killing efficacy of tigecycline to MRSA. The combination of isoniazid and tigecycline reduces the minimal inhibitory concentration of clinic MRSA strains to tigecycline. The killing activity of tigecycline is further confirmed by killing experiments and murine infection model. We further demonstrate the mechanism that isoniazid increases intracellular accumulation of tigecycline by promoting the influx but limiting the efflux of tigecycline through proton motive force. We also show that isoniazid and tigecycline synergize to increase the abundance of isoniazid-NAD adduct, which in turn damage cell membrane, possibly contributing to the disruption of PMF. Whereas phosphatidylethanolamine and cardiolipin are able to abrogate the synergistic effect of isoniazid plus tigecycline. Thus our study provides a new perspective that antibiotics, e.g. isoniazid, once recognized only to target Mycobacterium tuberculosis, can be repurposed as antibiotic adjuvant to tigecycline, expanding our choice of antibiotic-antibiotic combinations in treating bacterial infectious diseases.

异烟肼能增强替加环素杀死耐甲氧西林金黄色葡萄球菌的能力。
由于耐甲氧西林金黄色葡萄球菌(MRSA)对目前可用的广谱抗生素具有耐药性,因此迫切需要治疗耐甲氧西林金黄色葡萄球菌感染的方法。在此,我们报告了异烟肼能够增强替加环素对 MRSA 的杀灭效力。异烟肼和替加环素联合使用可降低临床 MRSA 菌株对替加环素的最小抑菌浓度。杀灭实验和小鼠感染模型进一步证实了替加环素的杀灭活性。我们进一步证明了异烟肼通过质子动力促进替加环素的流入而限制其流出,从而增加替加环素在细胞内蓄积的机制。我们还发现,异烟肼和替加环素协同增加了异烟肼-NAD加合物的丰度,进而破坏细胞膜,可能导致 PMF 的破坏。而磷脂酰乙醇胺和心磷脂则能减弱异烟肼和替加环素的协同作用。因此,我们的研究提供了一个新的视角,即曾经被认为只能针对结核分枝杆菌的抗生素,如异烟肼,可以被重新用作替加环素的抗生素辅助剂,从而扩大了我们在治疗细菌感染性疾病时抗生素-抗生素组合的选择范围。
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
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.
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