Targeting Latent Tuberculosis Using Hypoxia-Activated Prodrugs of Bedaquiline Analogues

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-03 DOI:10.1021/acsmedchemlett.6c00238

Christine G. Kim, Michael P. Hay, Robert F. Anderson, Sisira Kumara, Scott G. Franzblau, Christopher B. Cooper, Jiney Jose, Peter J. Choi

{"title":"Targeting Latent Tuberculosis Using Hypoxia-Activated Prodrugs of Bedaquiline Analogues","authors":"Christine G. Kim, Michael P. Hay, Robert F. Anderson, Sisira Kumara, Scott G. Franzblau, Christopher B. Cooper, Jiney Jose, Peter J. Choi","doi":"10.1021/acsmedchemlett.6c00238","DOIUrl":null,"url":null,"abstract":"<p>The increasing emergence\r\nof antimicrobial resistance (AMR) is reducing\r\nthe effectiveness of existing antibiotics against bacterial infections,\r\nincluding tuberculosis (TB), a deadly disease caused by Mycobacterium\r\ntuberculosis (M.tb). Approximately 90% of infected individuals develop\r\nlatent tuberculosis infection, for which current treatment options\r\nare limited. Latent tuberculosis infection is characterised by the\r\nformation of hypoxic granulomas, which restrict oxygen and drug penetration,\r\nhighlighting the need for therapies effective under hypoxic conditions.\r\nIn this study, a hypoxia-activated prodrug (HAP) strategy was\r\nemployed to improve selective drug delivery of promising anti-tuberculosis\r\ndrugs bedaquiline, TBAJ-587 and TBAJ-876 (sorfequiline) to hypoxic\r\nTB granulomas. Thirty-six nitroimidazole-based hypoxia-activated\r\nprodrugs (HAPs) were successfully synthesized and evaluated for antitubercular\r\nactivity. The HAPs exhibited potent <em>in vitro</em> activity\r\nunder both oxic and hypoxic conditions, with consistently lower MIC\r\nvalues observed in the hypoxic assays. Assessment of hypoxic selectivity\r\ndemonstrated enhanced trigger cleavage under hypoxic conditions, providing\r\nstrong evidence for the hypoxia-selective activation of these compounds.\r\n Collectively, these findings highlight the therapeutic potential\r\nof hypoxia-mediated strategies for the treatment of latent tuberculosis,\r\nparticularly within hypoxic niches that drive disease persistence\r\nand prolonged treatment regimens.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2140–2152"},"PeriodicalIF":3.9000,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.6c00238","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/9/3 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

The increasing emergence of antimicrobial resistance (AMR) is reducing the effectiveness of existing antibiotics against bacterial infections, including tuberculosis (TB), a deadly disease caused by Mycobacterium tuberculosis (M.tb). Approximately 90% of infected individuals develop latent tuberculosis infection, for which current treatment options are limited. Latent tuberculosis infection is characterised by the formation of hypoxic granulomas, which restrict oxygen and drug penetration, highlighting the need for therapies effective under hypoxic conditions. In this study, a hypoxia-activated prodrug (HAP) strategy was employed to improve selective drug delivery of promising anti-tuberculosis drugs bedaquiline, TBAJ-587 and TBAJ-876 (sorfequiline) to hypoxic TB granulomas. Thirty-six nitroimidazole-based hypoxia-activated prodrugs (HAPs) were successfully synthesized and evaluated for antitubercular activity. The HAPs exhibited potent in vitro activity under both oxic and hypoxic conditions, with consistently lower MIC values observed in the hypoxic assays. Assessment of hypoxic selectivity demonstrated enhanced trigger cleavage under hypoxic conditions, providing strong evidence for the hypoxia-selective activation of these compounds. Collectively, these findings highlight the therapeutic potential of hypoxia-mediated strategies for the treatment of latent tuberculosis, particularly within hypoxic niches that drive disease persistence and prolonged treatment regimens.

查看原文本刊更多论文

低氧激活贝达喹啉类似物前药靶向潜伏性结核

抗菌素耐药性（AMR）的日益出现正在降低现有抗生素对细菌感染的有效性，包括结核病（TB），一种由结核分枝杆菌（M.tb）引起的致命疾病。大约90%的感染者发展为结核感染，目前的治疗方案有限。潜伏性结核感染的特点是形成缺氧肉芽肿，这限制了氧气和药物的渗透，强调需要在缺氧条件下有效的治疗。在这项研究中，采用缺氧激活的前药（HAP）策略来改善有前途的抗结核药物贝达喹啉，TBAJ-587和TBAJ-876（索非喹啉）对缺氧结核肉芽肿的选择性给药。成功合成了36种以硝基咪唑为基础的低氧激活前药，并对其抗结核活性进行了评价。HAPs在缺氧和缺氧条件下都表现出强大的体外活性，在缺氧试验中观察到的mich值始终较低。对低氧选择性的评估表明，在低氧条件下，触发裂解增强，为这些化合物的低氧选择性激活提供了强有力的证据。总的来说，这些发现强调了缺氧介导的治疗潜伏性结核病策略的治疗潜力，特别是在导致疾病持续和延长治疗方案的缺氧生态位中。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.