Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome

Jansen, Robert S.; Rhee, Kyu Y.

doi:10.1016/j.tips.2017.01.005

Cited by 25 publications

(20 citation statements)

References 79 publications

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“…We identified a number of central carbon metabolism genes with differential genetic requirements from our TnSeq data ( Fig 3 ). Bacterial metabolism has emerged as a promising target for antibiotic development [ 46 , 47 ] but our data suggests that molecules targeting these pathways may have variable efficacy across clinical strains. For example, the clinical strains varied in their requirement for glcB , which encodes malate synthase (GlcB), the second enzyme in the glyoxylate shunt ( Fig 3 , S7 Table ).…”

Section: Resultsmentioning

confidence: 99%

TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities

et al. 2018

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Once considered a phenotypically monomorphic bacterium, there is a growing body of work demonstrating heterogeneity among Mycobacterium tuberculosis (Mtb) strains in clinically relevant characteristics, including virulence and response to antibiotics. However, the genetic and molecular basis for most phenotypic differences among Mtb strains remains unknown. To investigate the basis of strain variation in Mtb, we performed genome-wide transposon mutagenesis coupled with next-generation sequencing (TnSeq) for a panel of Mtb clinical isolates and the reference strain H37Rv to compare genetic requirements for in vitro growth across these strains. We developed an analytic approach to identify quantitative differences in genetic requirements between these genetically diverse strains, which vary in genomic structure and gene content. Using this methodology, we found differences between strains in their requirements for genes involved in fundamental cellular processes, including redox homeostasis and central carbon metabolism. Among the genes with differential requirements were katG, which encodes the activator of the first-line antitubercular agent isoniazid, and glcB, which encodes malate synthase, the target of a novel small-molecule inhibitor. Differences among strains in their requirement for katG and glcB predicted differences in their response to these antimicrobial agents. Importantly, these strain-specific differences in antibiotic response could not be predicted by genetic variants identified through whole genome sequencing or by gene expression analysis. Our results provide novel insight into the basis of variation among Mtb strains and demonstrate that TnSeq is a scalable method to predict clinically important phenotypic differences among Mtb strains.

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Section: Resultsmentioning

confidence: 99%

TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities

et al. 2018

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“…Compound 1b exhibited no depletion from the media indicating a lack of uptake or rapid efflux (Supplementary Table 3). Compound 2b, in contrast, exhibited complete depletion from the media but accumulated in M. tuberculosis to levels that accounted for less than 2% of the amount consumed (Supplementary Table 3), indicative of its likely intrabacterial metabolism [36][37][38][39] . These results explain the observed differences in potency between the enzymatic assay and whole cell activity and shows that they are related to low compound permeation/high efflux for 1b and metabolism in the case of 2b.…”

Section: Resultsmentioning

confidence: 99%

Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site

et al. 2021

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Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.

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“…Certain constituents of the cell, such as mycolic acids, arabinogalactan, peptidoglycan and mycobactin, may represent specific targets for new anti-TB drugs [ 37 , 92 ]. Many compounds that inhibit specific steps in either arabinogalactan or mycolic acid biosynthesis have been discovered [ 93 ]. Novel efficacious and safe anti-TB drugs are currently needed so as: to shorten the duration of TB therapy; treat MDR, XDR and totally drug resistant (TDR) TB strains; and latent TB; act synergistically with other co-administered anti-TB drugs; and, finally, to be safely co-administered with anti-HIV agents [ 37 ].…”

Section: Metabolomics Approaches and Its Application To Medicinal Plamentioning

confidence: 99%

Application of metabolomics to drug discovery and understanding the mechanisms of action of medicinal plants with anti‐tuberculosis activity

Tuyiringire

Tusubira

Munyampundu

et al. 2018

Clinical & Translational Med

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Human tuberculosis (TB) is amongst the oldest and deadliest human bacterial diseases that pose major health, social and economic burden at a global level. Current regimens for TB treatment are lengthy, expensive and ineffective to emerging drug resistant strains. Thus, there is an urgent need for identification and development of novel TB drugs and drug regimens with comprehensive and specific mechanisms of action. Many medicinal plants are traditionally used for TB treatment. While some of their phytochemical composition has been elucidated, their mechanisms of action are not well understood. Insufficient knowledge on Mycobacterium tuberculosis ( M.tb ) biology and the complex nature of its infection limit the effectiveness of current screening-based methods used for TB drug discovery. Nonetheless, application of metabolomics tools within the ‘omics’ approaches, could provide an alternative method of elucidating the mechanism of action of medicinal plants. Metabolomics aims at high throughput detection, quantification and identification of metabolites in biological samples. Changes in the concentration of specific metabolites in a biological sample indicate changes in the metabolic pathways. In this paper review and discuss novel methods that involve application of metabolomics to drug discovery and the understanding of mechanisms of action of medicinal plants with anti-TB activity. Current knowledge on TB infection, anti-TB drugs and mechanisms of action are also included. We further highlight metabolism of M. tuberculosis and the potential drug targets, as well as current approaches in the development of anti-TB drugs.

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Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome

Cited by 25 publications

References 79 publications

TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities

TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities

Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site

Application of metabolomics to drug discovery and understanding the mechanisms of action of medicinal plants with anti‐tuberculosis activity

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