{"title":"Novobiocin primarily targets ParE in Neisseria gonorrhoeae.","authors":"Yoshimasa Ishizaki, Chigusa Hayashi, Kazuaki Matoba, Masayuki Igarashi","doi":"10.1038/s41429-024-00797-1","DOIUrl":null,"url":null,"abstract":"<p><p>Multidrug-resistant Neisseria gonorrhoeae is a pathogenic bacterium that poses a public health concern. In this study, we aimed to elucidate the mode of action of the conventional antibiotic novobiocin, which has been selected as a leading compound for novel antigonococcal drugs. Unlike other previously studied bacteria strains, novobiocin-resistant N. gonorrhoeae strains have a mutation in the parE gene encoding DNA topoisomerase IV, strongly implying that the primary target of novobiocin is DNA topoisomerase IV and not DNA gyrase. The construction of genetically modified strains and structural biology analysis in silico suggest that this target discrepancy is from variations in the amino acid sequences in GyrB (Ile 78 in Escherichia coli, Met82 in N. gonorrhoeae) and ParE (Met 74 in E. coli, Ile76 in N. gonorrhoeae). This finding contributes to the development of drugs that target both GyrB and ParE enzymes to a similar extent.</p>","PeriodicalId":54884,"journal":{"name":"Journal of Antibiotics","volume":" ","pages":""},"PeriodicalIF":2.1000,"publicationDate":"2024-12-16","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/s41429-024-00797-1","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
Multidrug-resistant Neisseria gonorrhoeae is a pathogenic bacterium that poses a public health concern. In this study, we aimed to elucidate the mode of action of the conventional antibiotic novobiocin, which has been selected as a leading compound for novel antigonococcal drugs. Unlike other previously studied bacteria strains, novobiocin-resistant N. gonorrhoeae strains have a mutation in the parE gene encoding DNA topoisomerase IV, strongly implying that the primary target of novobiocin is DNA topoisomerase IV and not DNA gyrase. The construction of genetically modified strains and structural biology analysis in silico suggest that this target discrepancy is from variations in the amino acid sequences in GyrB (Ile 78 in Escherichia coli, Met82 in N. gonorrhoeae) and ParE (Met 74 in E. coli, Ile76 in N. gonorrhoeae). This finding contributes to the development of drugs that target both GyrB and ParE enzymes to a similar extent.
耐多药淋病奈瑟菌是一种病原菌，对公共健康构成威胁。在本研究中，我们旨在阐明传统抗生素新生物素的作用模式，该抗生素已被选为新型抗淋球菌药物的主要化合物。与之前研究的其他菌株不同，耐新生物素的淋球菌菌株在编码 DNA 拓扑异构酶 IV 的 parE 基因上发生了突变，这强烈暗示了新生物素的主要作用靶点是 DNA 拓扑异构酶 IV，而不是 DNA 回旋酶。转基因菌株的构建和结构生物学分析表明，这一靶标差异来自于 GyrB（大肠杆菌中为 Ile 78，淋病双球菌中为 Met82）和 ParE（大肠杆菌中为 Met 74，淋病双球菌中为 Ile76）氨基酸序列的变异。这一发现有助于开发以类似程度的 GyrB 和 ParE 酶为靶标的药物。
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.
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