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Mechanism and resistance for antimycobacterial activity of a fluoroquinophenoxazine compound.

التفاصيل البيبلوغرافية
العنوان: Mechanism and resistance for antimycobacterial activity of a fluoroquinophenoxazine compound.
المؤلفون: Pamela K Garcia, Thirunavukkarasu Annamalai, Wenjie Wang, Raven S Bell, Duc Le, Paula Martin Pancorbo, Sabah Sikandar, Ahmed Seddek, Xufen Yu, Dianqing Sun, Anne-Catrin Uhlemann, Purushottam B Tiwari, Fenfei Leng, Yuk-Ching Tse-Dinh
المصدر: PLoS ONE, Vol 14, Iss 2, p e0207733 (2019)
بيانات النشر: Public Library of Science (PLoS), 2019.
سنة النشر: 2019
المجموعة: LCC:Medicine
LCC:Science
مصطلحات موضوعية: Medicine, Science
الوصف: We have previously reported the inhibition of bacterial topoisomerase I activity by a fluoroquinophenoxazine compound (FP-11g) with a 6-bipiperidinyl lipophilic side chain that exhibited promising antituberculosis activity (MIC = 2.5 μM against Mycobacterium tuberculosis, SI = 9.8). Here, we found that the compound is bactericidal towards Mycobacterium smegmatis, resulting in greater than 5 Log10 reduction in colony-forming units [cfu]/mL following a 10 h incubation at 1.25 μM (4X MIC) concentration. Growth inhibition (MIC = 50 μM) and reduction in cfu could also be observed against a clinical isolate of Mycobacterium abscessus. Stepwise isolation of resistant mutants of M. smegmatis was conducted to explore the mechanism of resistance. Mutations in the resistant isolates were identified by direct comparison of whole-genome sequencing data from mutant and wild-type isolates. These include mutations in genes likely to affect the entry and retention of the compound. FP-11g inhibits Mtb topoisomerase I and Mtb gyrase with IC50 of 0.24 and 27 μM, respectively. Biophysical analysis showed that FP-11g binds DNA as an intercalator but the IC50 for inhibition of Mtb topoisomerase I activity is >10 fold lower than the compound concentrations required for producing negatively supercoiled DNA during ligation of nicked circular DNA. Thus, the DNA-binding property of FP-11g may contribute to its antimycobacterial mechanism, but that alone cannot account for the observed inhibition of Mtb topoisomerase I.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1932-6203
Relation: https://doaj.org/toc/1932-6203
DOI: 10.1371/journal.pone.0207733
URL الوصول: https://doaj.org/article/d9bfda57d9f048fe980faa0d20768f76
رقم الأكسشن: edsdoj.9bfda57d9f048fe980faa0d20768f76
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:19326203
DOI:10.1371/journal.pone.0207733