This significant characteristic makes possible the relatively rapid elimination of bacteria which otherwise would require treatment for extended periods (6 to 8 months). These have shown to be active against both replicative and hypoxic non-replicating bacilli 1, 2. This search for anti-mycobacterials has identified the very promising bicyclic nitroimidazoles pretomanid (PA-824) and delamanid (OPC-67683), which are currently in clinical phase III with the Global Alliance for TB Drug Development. As a result, the pursuit for new anti-mycobacterials has accelerated in recent years. Tuberculosis (TB) persists as a major global threat, mostly amongst people infected with antibiotic resistant forms of Mycobacterium tuberculosis, the causal agent of the disease 1. This compound showed significant antimicrobial activity (MIC 0.65 mM) against M. These effects were linked to the accumulation of a toxic metabolite methylglyoxal. This targeted the pentose phosphate pathway with significant accumulation seen with fructose-6-phosphate, ribose-5-phosphate and glyceraldehyde-3-phosphate. Metabolites which differed significantly only with pretomanid treatment were identified and mapped on to bacterial metabolic pathways. Pretomanid treatments generated a unique distinctive metabolite profile when compared to ampicillin, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, rifampicin and streptomycin. The identification of key metabolites was independently confirmed by gas-chromatography time-of flight mass spectrometry (GC-tofMS) in comparison to standards. Untargeted high-resolution metabolite profiling was carried out using flow infusion electrospray ion high resolution mass spectrometry (FIE-HRMS) to identify and quantify metabolites. This study aimed to: (i) reveal the metabolome of Mycobacterium smegmatis under pretomanid treatment (ii) compare major sources of metabolite variation in bacteria treated with pretomanid treatment and other antibiotics and (iii) to target metabolites responsible for the killing activity of pretomanid in mycobacteria. Pretomanid is a promising anti-tubercular drug currently at clinical phase III, but its mechanisms of action are currently unclear.
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