Van T. Nguyen, Biruk T. Birhanu, Vega Miguel-Ruano, Choon Kim, Mayte Batuecas, Jingdong Yang, Amr M. El-Araby, Eva Jiménez-Faraco, Valerie A. Schroeder, Alejandra Alba, Neha Rana, Safaa Sader, Caitlyn A. Thomas, Rhona Feltzer, Mijoon Lee, Jed F. Fisher, Juan A. Hermoso, Mayland Chang, Shahriar Mobashery
{"title":"恢复耐甲氧西林金黄色葡萄球菌对β-内酰胺类抗生素的敏感性","authors":"Van T. Nguyen, Biruk T. Birhanu, Vega Miguel-Ruano, Choon Kim, Mayte Batuecas, Jingdong Yang, Amr M. El-Araby, Eva Jiménez-Faraco, Valerie A. Schroeder, Alejandra Alba, Neha Rana, Safaa Sader, Caitlyn A. Thomas, Rhona Feltzer, Mijoon Lee, Jed F. Fisher, Juan A. Hermoso, Mayland Chang, Shahriar Mobashery","doi":"10.1038/s41589-024-01688-0","DOIUrl":null,"url":null,"abstract":"<p>Infections by <i>Staphylococcus aureus</i> have been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant <i>S. aureus</i> by acquisition of the <i>bla</i> and <i>mec</i> operons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate <b>4</b>. The X-ray structure of <b>4</b> is covalently engaged with the active-site serine of BlaR. Compound <b>4</b> potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant <i>S. aureus</i> strains. The combination of <b>4</b> with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"66 1","pages":""},"PeriodicalIF":12.9000,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus\",\"authors\":\"Van T. Nguyen, Biruk T. Birhanu, Vega Miguel-Ruano, Choon Kim, Mayte Batuecas, Jingdong Yang, Amr M. El-Araby, Eva Jiménez-Faraco, Valerie A. Schroeder, Alejandra Alba, Neha Rana, Safaa Sader, Caitlyn A. Thomas, Rhona Feltzer, Mijoon Lee, Jed F. Fisher, Juan A. Hermoso, Mayland Chang, Shahriar Mobashery\",\"doi\":\"10.1038/s41589-024-01688-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Infections by <i>Staphylococcus aureus</i> have been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant <i>S. aureus</i> by acquisition of the <i>bla</i> and <i>mec</i> operons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate <b>4</b>. The X-ray structure of <b>4</b> is covalently engaged with the active-site serine of BlaR. Compound <b>4</b> potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant <i>S. aureus</i> strains. The combination of <b>4</b> with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.</p><figure></figure>\",\"PeriodicalId\":18832,\"journal\":{\"name\":\"Nature chemical biology\",\"volume\":\"66 1\",\"pages\":\"\"},\"PeriodicalIF\":12.9000,\"publicationDate\":\"2024-07-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature chemical biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s41589-024-01688-0\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature chemical biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41589-024-01688-0","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus
Infections by Staphylococcus aureus have been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.
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