{"title":"TBAJ-587 是一种新型二芳基喹啉,对脓肿分枝杆菌具有活性。","authors":"Junsheng Fan, Zhili Tan, Siyuan He, Anqi Li, Yaping Jia, Juan Li, Zhemin Zhang, Bing Li, Haiqing Chu","doi":"10.1128/aac.00945-24","DOIUrl":null,"url":null,"abstract":"<p><p>Nontuberculous mycobacteria (NTM) infections are extremely difficult to treat due to a natural resistance to many antimicrobials. TBAJ-587 is a novel diarylquinoline, which shows higher anti-tuberculosis activity, lower lipophilicity, and weaker inhibition of hERG channels than bedaquiline (BDQ). The susceptibilities of 11 NTM reference strains and 194 clinical <i>Mycobacterium abscessus</i> isolates to TBAJ-587 were determined by the broth microdilution assay. The activity of TBAJ-587 toward the growth of <i>M. abscessus</i> in macrophages was also evaluated. Minimum bactericidal concentration and time-kill kinetic assays were conducted to distinguish between the bactericidal and bacteriostatic activities of TBAJ-587. The synergy between TBAJ-587 and eight clinically important antibiotics was determined using a checkerboard assay. TBAJ-587 was highly effective against <i>M. abscessus</i> by targeting its F-ATP synthase <i>c</i> chain. The antimicrobial activities of TBAJ-587 and BDQ toward intracellular <i>M. abscessus</i> were comparable. The <i>in vivo</i> activities of TBAJ-587 and BDQ in an immunocompromised mouse model were also comparable. TBAJ-587 expressed bactericidal activity and was compatible with eight anti-NTM drugs commonly used in clinical practice; no antagonism was discovered. As such, TBAJ-587 represents a potential candidate for the treatment of NTM infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0094524"},"PeriodicalIF":4.1000,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619292/pdf/","citationCount":"0","resultStr":"{\"title\":\"TBAJ-587, a novel diarylquinoline, is active against <i>Mycobacterium abscessus</i>.\",\"authors\":\"Junsheng Fan, Zhili Tan, Siyuan He, Anqi Li, Yaping Jia, Juan Li, Zhemin Zhang, Bing Li, Haiqing Chu\",\"doi\":\"10.1128/aac.00945-24\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Nontuberculous mycobacteria (NTM) infections are extremely difficult to treat due to a natural resistance to many antimicrobials. TBAJ-587 is a novel diarylquinoline, which shows higher anti-tuberculosis activity, lower lipophilicity, and weaker inhibition of hERG channels than bedaquiline (BDQ). The susceptibilities of 11 NTM reference strains and 194 clinical <i>Mycobacterium abscessus</i> isolates to TBAJ-587 were determined by the broth microdilution assay. The activity of TBAJ-587 toward the growth of <i>M. abscessus</i> in macrophages was also evaluated. Minimum bactericidal concentration and time-kill kinetic assays were conducted to distinguish between the bactericidal and bacteriostatic activities of TBAJ-587. The synergy between TBAJ-587 and eight clinically important antibiotics was determined using a checkerboard assay. TBAJ-587 was highly effective against <i>M. abscessus</i> by targeting its F-ATP synthase <i>c</i> chain. The antimicrobial activities of TBAJ-587 and BDQ toward intracellular <i>M. abscessus</i> were comparable. The <i>in vivo</i> activities of TBAJ-587 and BDQ in an immunocompromised mouse model were also comparable. TBAJ-587 expressed bactericidal activity and was compatible with eight anti-NTM drugs commonly used in clinical practice; no antagonism was discovered. As such, TBAJ-587 represents a potential candidate for the treatment of NTM infections.</p>\",\"PeriodicalId\":8152,\"journal\":{\"name\":\"Antimicrobial Agents and Chemotherapy\",\"volume\":\" \",\"pages\":\"e0094524\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-12-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619292/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Antimicrobial Agents and Chemotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1128/aac.00945-24\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/29 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antimicrobial Agents and Chemotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1128/aac.00945-24","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/29 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
TBAJ-587, a novel diarylquinoline, is active against Mycobacterium abscessus.
Nontuberculous mycobacteria (NTM) infections are extremely difficult to treat due to a natural resistance to many antimicrobials. TBAJ-587 is a novel diarylquinoline, which shows higher anti-tuberculosis activity, lower lipophilicity, and weaker inhibition of hERG channels than bedaquiline (BDQ). The susceptibilities of 11 NTM reference strains and 194 clinical Mycobacterium abscessus isolates to TBAJ-587 were determined by the broth microdilution assay. The activity of TBAJ-587 toward the growth of M. abscessus in macrophages was also evaluated. Minimum bactericidal concentration and time-kill kinetic assays were conducted to distinguish between the bactericidal and bacteriostatic activities of TBAJ-587. The synergy between TBAJ-587 and eight clinically important antibiotics was determined using a checkerboard assay. TBAJ-587 was highly effective against M. abscessus by targeting its F-ATP synthase c chain. The antimicrobial activities of TBAJ-587 and BDQ toward intracellular M. abscessus were comparable. The in vivo activities of TBAJ-587 and BDQ in an immunocompromised mouse model were also comparable. TBAJ-587 expressed bactericidal activity and was compatible with eight anti-NTM drugs commonly used in clinical practice; no antagonism was discovered. As such, TBAJ-587 represents a potential candidate for the treatment of NTM infections.
期刊介绍:
Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.