Dataset Information

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.

ABSTRACT: Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in?vitro and in?vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

SUBMITTER: Liu R

PROVIDER: S-EPMC5659129 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.

Liu Renhe R Lyu Xiaoxuan X Batt Sarah M SM Hsu Mei-Hui MH Harbut Michael B MB Vilchèze Catherine C Cheng Bo B Ajayi Kehinde K Yang Baiyuan B Yang Yun Y Guo Hui H Lin Changyou C Gan Fei F Wang Chen C Franzblau Scott G SG Jacobs William R WR Besra Gurdyal S GS Johnson Eric F EF Petrassi Mike M Chatterjee Arnab K AK Fütterer Klaus K Wang Feng F

Angewandte Chemie (International ed. in English) 20170907 42

Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound sho ...[more]

PMID: 28815830

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Project description:BackgroundThe success of tuberculosis treatment relies on patients adhering to their medication regimen consistently. However, adherence levels tend to decrease among patients who experience adverse drug reactions to antitubercular medications, leading to suboptimal treatment outcomes. Hence, this study aimed to examine the types, incidence rates, and severity of adverse reactions caused by first-line antitubercular drugs. Additionally, it aimed to identify factors associated with the development of these reactions. By doing so, the study aimed to facilitate the provision of personalized and effective treatment to patients, ultimately improving treatment outcomes.MethodsNewly diagnosed patients with active tuberculosis were monitored from the start of their treatment until the completion of therapy. Any adverse reactions to anti-TB drugs that they encountered were carefully recorded. The collected data were analyzed using appropriate statistical methods such as analysis of variance, Chi-squared test, Fisher's exact test, and independent t-tests. Logistic regression was employed to assess the association between adverse drug reactions and various socio-demographic and clinical factors of the patients, using odds ratios as a measure of association.ResultsAmong the 378 patients included in the study, 181 individuals (47.9%) reported experiencing at least one adverse drug reaction, with an incidence rate of 1.75 events per 100-person months. The majority of these reactions occurred during the intensive phase of treatment. The gastrointestinal tract was the most commonly affected system, followed by the nervous system and skin. Patients aged over 45 years (OR = 1.55, 95% CI 1.01-2.39, p = 0.046) and those with extrapulmonary tuberculosis (OR = 2.41, 95% CI 1.03-5.64) were more likely to develop gastrointestinal reactions. Female gender was a significant predictor of both skin (OR = 1.78, 95% CI 1.05-3.02, p = 0.032) and nervous system (OR = 1.65, 95% CI 1.07-2.55, p = 0.024) reactions. Additionally, alcohol use and HIV infection were identified as independent predictors of adverse drug reactions affecting all three systems.ConclusionSignificant risk factors for developing antitubercular drug adverse reactions include alcohol consumption, cigarette smoking, being HIV positive, female gender and extrapulmonary tuberculosis.

Dataset Information

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.

Publications

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.

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