一种使耐药革兰氏阳性细菌对恶唑烷类抗生素重新敏感的策略。

IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
EBioMedicine Pub Date : 2025-09-01 Epub Date: 2025-09-04 DOI:10.1016/j.ebiom.2025.105914
Qi Zhang, Yang Yang, Ying Yang, Jin Shang, Shan Su, Peng Gao, Xiao-Xiao Li, Zhao Liu, Richard Yi-Tsun Kao, Ben Chi-Bun Ko, Benjamin Thompson, Qian Zhao
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引用次数: 0

摘要

背景:耐多药细菌感染死亡率高,治疗选择少。协同组合可能改善临床结果,但传统策略往往损害健康的微生物群。恶唑烷酮类抗生素是治疗耐药细菌感染的典型最后手段,但由于耐药性的发展而变得不那么有效。方法:在高通量筛选后,通过体外指标(如分数抑制浓度指数、生物膜形成和耐药性发展)和皮肤和眼部细菌感染动物的体内症状(以及眼部微生物组提取分析)进一步评估协同作用。利用蛋白质组学、化学合成、多显微技术和抗生素实时/动态积累技术来探索其机制并扩大转化应用。结果:将磷酸化的恶唑烷类抗生素与带正电荷的化合物(溶菌酶为原生代表)联合使用可导致广谱药物再致敏。在典型的组合中,尿素循环被破坏,使细胞质碱化,随后激活碱性磷酸酶,促进磷酸化的前药转化为活性形式。通过引入恢复健康微生物组的概念作为抗生素治疗的评估指标,我们证实了该策略在临床环境中具有良好的转化和微生物友好潜力,因为它不仅在体外抑制生物膜的形成和耐药突变的发展,而且还缓解了感染动物的症状,包括恢复健康的微生物组。解释:由于这两种药物都具有良好的安全性,因此可以立即考虑在人体中进行此类临床研究。换句话说,科学家们从这种策略中获益,因为它同时获得了更大的功效(500倍的再致敏)和更高的安全性(基于前药物和微生物友好的策略,特别是当活性形式可能有毒时)。资助:研究资助局合作研究基金(C5033-19E)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A strategy to re-sensitise drug-resistant Gram-positive bacteria to oxazolidinone-class antibiotics.

Background: Multidrug-resistant bacterial infections have high mortality rates and few treatment options. Synergistic combinations may improve clinical outcome but traditional strategies often damage healthy microbiome. Oxazolidinone-class antibiotics are typical last-resort drugs for treating drug-resistant bacterial infections but are becoming less effective due to resistance development.

Methods: After high-throughput screening, synergy was further assessed by in vitro indices (like fractional inhibitory concentration index, biofilm formation and resistance development) and in vivo symptoms in animals with skin and ocular bacterial infections (and ocular microbiome extraction analysis). Proteomics, chemical synthesis, multi-microscopy techniques and antibiotic real-time/kinetic accumulation were employed to explore mechanisms and expand translational applications.

Findings: Combining phosphorylated oxazolidinone-class antibiotics with positively charged compounds (lysozyme as native representative) resulted in broad-spectrum drug re-sensitisation. In representative combination, urea cycle was disrupted to alkalinise cytoplasm, which subsequently activated alkaline phosphatase to promote conversion of phosphorylated prodrug to active form. By introducing concept of restored healthy microbiome as the evaluated index in antibiotic therapy, we confirmed excellent translational and microbiome-friendly potential of this strategy in clinical settings because it not only inhibited biofilm formation and development of drug-resistant mutations in vitro, but also alleviated symptoms in infected animals including the restoration of healthy microbiome.

Interpretation: As both agents have excellent safety profiles, such clinical investigation may immediately be contemplated in humans. Translationally, scientists benefit from strategy by simultaneously achieving greater efficacy (>500-fold re-sensitisation) and higher safety (prodrug-based and microbiome-friendly strategy especially when active form may be toxic).

Funding: Collaborative Research Funds from Research Grants Council (C5033-19E).

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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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