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Improved Phenoxyalkylbenzimidazoles with Activity against Mycobacterium tuberculosis Appear to Target QcrB
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-10-31 00:00:00 , DOI: 10.1021/acsinfecdis.7b00112 N. Susantha Chandrasekera 1 , Bryan J. Berube 1 , Gauri Shetye 1 , Somsundaram Chettiar 1 , Theresa O’Malley 1 , Alyssa Manning 1 , Lindsay Flint 1 , Divya Awasthi 1 , Thomas R. Ioerger , James Sacchettini , Thierry Masquelin 2 , Philip A. Hipskind 2 , Joshua Odingo 1 , Tanya Parish 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-10-31 00:00:00 , DOI: 10.1021/acsinfecdis.7b00112 N. Susantha Chandrasekera 1 , Bryan J. Berube 1 , Gauri Shetye 1 , Somsundaram Chettiar 1 , Theresa O’Malley 1 , Alyssa Manning 1 , Lindsay Flint 1 , Divya Awasthi 1 , Thomas R. Ioerger , James Sacchettini , Thierry Masquelin 2 , Philip A. Hipskind 2 , Joshua Odingo 1 , Tanya Parish 1
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The phenoxy alkyl benzimidazoles (PABs) have good antitubercular activity. We expanded our structure–activity relationship studies to determine the core components of PABs required for activity. The most potent compounds had minimum inhibitory concentrations against Mycobacterium tuberculosis in the low nanomolar range with very little cytotoxicity against eukaryotic cells as well as activity against intracellular bacteria. We isolated resistant mutants against PAB compounds, which had mutations in either Rv1339, of unknown function, or qcrB, a component of the cytochrome bc1 oxidase of the electron transport chain. QcrB mutant strains were resistant to all PAB compounds, whereas Rv1339 mutant strains were only resistant to a subset, suggesting that QcrB is the target. The discovery of the target for PAB compounds will allow for the improved design of novel compounds to target intracellular M. tuberculosis.
中文翻译：
具有抗结核分枝杆菌活性的改进的苯氧基烷基苯并咪唑类药物出现在目标QcrB上
苯氧基烷基苯并咪唑（PAB）具有良好的抗结核活性。我们扩展了结构-活性关系研究，以确定活性所需的PAB的核心成分。最有效的化合物在低纳摩尔浓度范围内具有最小的结核分枝杆菌抑制浓度，对真核细胞的细胞毒性很小，对细胞内细菌的活性也很小。我们分离了针对PAB化合物的抗性突变体，该化合物在Rv1339中具有未知功能或qcrB（细胞色素bc 1的组成部分）中的突变电子传输链的氧化酶。QcrB突变株对所有PAB化合物均具有抗性，而Rv1339突变株仅对子集具有抗性，表明QcrB是靶标。PAB化合物靶标的发现将使得新型化合物靶向细胞内结核分枝杆菌的设计得到改进。
更新日期：2017-10-31
中文翻译：
具有抗结核分枝杆菌活性的改进的苯氧基烷基苯并咪唑类药物出现在目标QcrB上
苯氧基烷基苯并咪唑（PAB）具有良好的抗结核活性。我们扩展了结构-活性关系研究，以确定活性所需的PAB的核心成分。最有效的化合物在低纳摩尔浓度范围内具有最小的结核分枝杆菌抑制浓度，对真核细胞的细胞毒性很小，对细胞内细菌的活性也很小。我们分离了针对PAB化合物的抗性突变体，该化合物在Rv1339中具有未知功能或qcrB（细胞色素bc 1的组成部分）中的突变电子传输链的氧化酶。QcrB突变株对所有PAB化合物均具有抗性，而Rv1339突变株仅对子集具有抗性，表明QcrB是靶标。PAB化合物靶标的发现将使得新型化合物靶向细胞内结核分枝杆菌的设计得到改进。
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