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Description
Mycobacterium tuberculosis (Mtb) is the most-deadly human pathogen in the world, killing over a million people annually. Although antibiotic treatments can cure Tuberculosis (TB), the rise in multidrug resistance has exacerbated the endemic. One area of research that has gained traction as a means to better understand Mtb pathogenicity and the development of antibiotic resistance is metabolism. In particular, genome-scale metabolic modeling has emerged as a useful tool for assessing Mtb metabolism in silico. In this study, we used an updated genome-scale metabolic model of Mtb to identify metabolites capable of overcoming growth inhibition brought forth by first-line TB drugs (rifampicin excluded). These metabolites were then associated with metabolic reactions and pathways to develop testable hypotheses as to how antibiotic resistance may develop in Mtb. A genome-scale metabolic model, iEK1008, was updated based on the literature and genome annotation for Mtb strain H37Rv to construct iMtb_H37Rv_1132, which contains 1,132 genes, 1,407 reactions, and 1,078 metabolites (a 15% increase in the metabolic network). After considerable curation, iMtb_H37Rv_1132 achieved an accuracy of 91% compared to seven TB drugs with enzymatic targets, 89% compared to a single Biolog experiment, 82% compared to ten transposon mutant libraries of H37Rv, and an overall MEMOTE score of 91%. To develop testable hypotheses related to antibiotic resistance in Mtb, 294 metabolites in at least one orphan reaction were evaluated. No single metabolite was able to overcome growth inhibition induced by isoniazid, ethambutol or all first-line TB drugs together, however, nine metabolites were able to overcome growth inhibition induced by pyrazinamide (PZA). Eight of these metabolites are part of a previously annotated coenzyme A (CoA) synthesis pathway in Mtb, but one metabolite, malonate semialdehyde, is hypothesized to be part of an unannotated metabolic pathway. If experimentally verified through Biolog experiments or enzymatic characterization studies, a malonate semialdehyde-mediated metabolic pathway may be a novel way in which Mtb bypasses PZA’s inhibition of CoA synthesis and confers resistance to PZA.
