Molecules, Vol. 25, Pages 415: Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase

Molecules, Vol. 25, Pages 415: Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase Molecules doi: 10.3390/molecules25020415 Authors: Elise Pierson Marie Haufroid Tannu Priya Gosain Pankaj Chopra Ramandeep Singh Johan Wouters Mycobacterium tuberculosis is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. M. tuberculosis phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen’s serine pathway, it appears to be involved in immune evasion mechanisms. In this work, a malachite green-based phosphatase assay has been used to screen 122 compounds from an internal chemolibrary. Trisubstituted harmine derivatives were found among the best hits that inhibited SerB2 activity. Synthesis of an original compound helped to discuss a brief structure activity relationship evaluation. Kinetics experiments showed that the most potent derivatives inhibit the phosphatase in a parabolic competitive fashion with apparent inhibition constants ( K i ) values in the micromolar range. Their interaction modes with the enzyme were investigated through induced fit docking experiments, leading to results consistent with the experimental data. Cellular assays showed that the selected compounds also inh...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research

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Abstract Comprehensive guidelines for treatment of latent tuberculosis infection (LTBI) among persons living in the United States were last published in 2000 (American Thoracic Society. CDC targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47). Since then, several new regimens have been evaluated in clinical trials. To update previous guidelines, the National Tuberculosis Controllers Association (NTCA) and CDC convened a committee to conduct a systematic literature review and make new recommendations for the most effective and least toxic regimens f...
Source: MMWR Recomm Rep - Category: Epidemiology Authors: Tags: MMWR Recomm Rep Source Type: research
Recently, the World Health Organization (WHO) released the updated guideline on the treatment for multi-drug resistant tuberculosis (MDR-TB) treatment regimens based on new experimental and observational evidence [1]. In this new guidance the most important drugs are the late-generation fluoroquinolones (i.e. levofloxacin and moxifloxacin), linezolid and bedaquiline. Despite the new guidance, MDR- and extensively drug resistant (XDR) TB treatment is challenging due to the risk of drug-related adverse events (AE) and drug–drug interactions (DDI). Precision medicine-based approach to minimise the risk of resistance eme...
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In this study, we identified Rv0023, an Mtb protein belonging to the xenobiotic response element (XRE) family of transcription regulators, which has a role in generating higher tolerance toward INH and ETH in Mycobacterium smegmatis (Msmeg). Overexpression of Rv0023 in Msmeg leads to the development of INH- and ETH-tolerant strains. The strains expressing Rv0023 have a higher ratio of NADH/NAD+, and this physiological event is known to play a crucial role in the development of INH/ETH co-resistance in Msmeg. Gene expression analysis of some target genes revealed reduction in the expression of the ndh gene, but no direct in...
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Abstract Tuberculosis (TB) is the foremost cause of mortality from single infectious agent Mycobacterium tuberculosis (MTB). Current therapeutic regimes suffer from several problems including side effects, costs and emergence of multidrug resistance (MDR). Moreover, conventional diagnostic methods are either too slow, lack accurate or robust biomarkers. Under such circumstances, identification of rapid metabolite based biomarkers as novel drug targets could be a potential approach to circumvent MDR. In the era of "OMIC" sciences, lipidomics has gain significant attention to unravel the complexity of lipi...
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