Exploration of vanoxerine analogues as antibacterial agents.

IF 2.1 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Antibiotics Pub Date : 2024-10-15 DOI:10.1038/s41429-024-00781-9

Alexander D H Kingdon, Holly V Adcock, Eleni-Marina Kasimati, Philip Craven, Willem van Schaik, Liam R Cox, Gurdyal S Besra

{"title":"Exploration of vanoxerine analogues as antibacterial agents.","authors":"Alexander D H Kingdon, Holly V Adcock, Eleni-Marina Kasimati, Philip Craven, Willem van Schaik, Liam R Cox, Gurdyal S Besra","doi":"10.1038/s41429-024-00781-9","DOIUrl":null,"url":null,"abstract":"<p><p>Mycobacterium tuberculosis is a bacterial pathogen, responsible for approximately 1.3 million deaths in 2022 through tuberculosis infections. The complex treatment regimen required to treat tuberculosis and growing rates of drug resistance, necessitates the development of new anti-mycobacterial agents. One approach is to repurpose drugs from other clinical applications. Vanoxerine (GBR 12909) was previously shown to have anti-mycobacterial activity, through dissipating the membrane electric potential and hence, cellular energetics. Several vanoxerine analogues were synthesised in this study, which exhibited a range of activities against mycobacteria and enterococcus. All active analogues had similar impacts on the membrane electric potential and inhibition of ethidium bromide efflux. The most active compound displayed reduced inhibitory activity against the known human target of vanoxerine, the dopamine transporter. This work has identified a promising analogue, which could provide a starting point for further medicinal chemistry and drug development efforts to target mycobacteria.</p>","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":" ","pages":""},"PeriodicalIF":2.1000,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Antibiotics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41429-024-00781-9","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Mycobacterium tuberculosis is a bacterial pathogen, responsible for approximately 1.3 million deaths in 2022 through tuberculosis infections. The complex treatment regimen required to treat tuberculosis and growing rates of drug resistance, necessitates the development of new anti-mycobacterial agents. One approach is to repurpose drugs from other clinical applications. Vanoxerine (GBR 12909) was previously shown to have anti-mycobacterial activity, through dissipating the membrane electric potential and hence, cellular energetics. Several vanoxerine analogues were synthesised in this study, which exhibited a range of activities against mycobacteria and enterococcus. All active analogues had similar impacts on the membrane electric potential and inhibition of ethidium bromide efflux. The most active compound displayed reduced inhibitory activity against the known human target of vanoxerine, the dopamine transporter. This work has identified a promising analogue, which could provide a starting point for further medicinal chemistry and drug development efforts to target mycobacteria.

查看原文本刊更多论文

探索作为抗菌剂的 vanoxerine 类似物。

结核分枝杆菌是一种细菌性病原体，2022 年约有 130 万人死于结核感染。治疗结核病所需的治疗方案十分复杂，而且耐药率越来越高，因此有必要开发新的抗分枝杆菌药物。其中一种方法是重新利用其他临床应用中的药物。凡诺瑟林（GBR 12909）以前曾被证明具有抗霉菌活性，其作用是消除膜电动势，从而降低细胞能量。本研究合成了几种凡诺瑟林类似物，它们对分枝杆菌和肠球菌具有不同的活性。所有活性类似物对膜电位和溴化乙锭外流抑制都有类似的影响。活性最强的化合物对已知的人类香草酸靶标--多巴胺转运体--的抑制活性有所降低。这项研究发现了一种很有前景的类似物，它可以为针对分枝杆菌的进一步药物化学和药物开发工作提供一个起点。

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

Journal of Antibiotics 医学-免疫学

CiteScore

6.60

自引率

3.00%

发文量

审稿时长

1 months

期刊介绍： The Journal of Antibiotics seeks to promote research on antibiotics and related types of biologically active substances and publishes Articles, Review Articles, Brief Communication, Correspondence and other specially commissioned reports. The Journal of Antibiotics accepts papers on biochemical, chemical, microbiological and pharmacological studies. However, studies regarding human therapy do not fall under the journal’s scope. Contributions regarding recently discovered antibiotics and biologically active microbial products are particularly encouraged. Topics of particular interest within the journal''s scope include, but are not limited to, those listed below: Discovery of new antibiotics and related types of biologically active substances Production, isolation, characterization, structural elucidation, chemical synthesis and derivatization, biological activities, mechanisms of action, and structure-activity relationships of antibiotics and related types of biologically active substances Biosynthesis, bioconversion, taxonomy and genetic studies on producing microorganisms, as well as improvement of production of antibiotics and related types of biologically active substances Novel physical, chemical, biochemical, microbiological or pharmacological methods for detection, assay, determination, structural elucidation and evaluation of antibiotics and related types of biologically active substances Newly found properties, mechanisms of action and resistance-development of antibiotics and related types of biologically active substances.