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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Oxazolidinone-class antibiotics are typical last-resort drugs for treating drug-resistant bacterial infections but are becoming less effective due to resistance development.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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).</p><p><strong>Funding: </strong>Collaborative Research Funds from Research Grants Council (C5033-19E).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105914"},"PeriodicalIF":10.8000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446384/pdf/","citationCount":"0","resultStr":"{\"title\":\"A strategy to re-sensitise drug-resistant Gram-positive bacteria to oxazolidinone-class antibiotics.\",\"authors\":\"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\",\"doi\":\"10.1016/j.ebiom.2025.105914\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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).</p><p><strong>Funding: </strong>Collaborative Research Funds from Research Grants Council (C5033-19E).</p>\",\"PeriodicalId\":11494,\"journal\":{\"name\":\"EBioMedicine\",\"volume\":\"119 \",\"pages\":\"105914\"},\"PeriodicalIF\":10.8000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446384/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EBioMedicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ebiom.2025.105914\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/9/4 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EBioMedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ebiom.2025.105914","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/9/4 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
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).
EBioMedicineBiochemistry, 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.