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Untargeted metabolomics reveals a new mode of action of pretomanid (PA-824)

Baptista, Rafael, Fazakerley, David M., Beckmann, Manfred, Baillie, Les and Mur, Luis A. J. 2018. Untargeted metabolomics reveals a new mode of action of pretomanid (PA-824). Scientific Reports 8 (1) , 5084. 10.1038/s41598-018-23110-1

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Abstract

Pretomanid is a promising anti-tubercular drug currently at clinical phase III, but its mechanisms of action are currently unclear. 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. Untargeted high-resolution metabolite profiling was carried out using flow infusion electrospray ion high resolution mass spectrometry (FIE-HRMS) to identify and quantify metabolites. The identification of key metabolites was independently confirmed by gas-chromatography time-of flight mass spectrometry (GC-tofMS) in comparison to standards. Pretomanid treatments generated a unique distinctive metabolite profile when compared to ampicillin, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, rifampicin and streptomycin. Metabolites which differed significantly only with pretomanid treatment were identified and mapped on to bacterial metabolic pathways. This targeted the pentose phosphate pathway with significant accumulation seen with fructose-6-phosphate, ribose-5-phosphate and glyceraldehyde-3-phosphate. These effects were linked to the accumulation of a toxic metabolite methylglyoxal. This compound showed significant antimicrobial activity (MIC 0.65 mM) against M. smegmatis.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Pharmacy
Publisher: Nature Publishing Group
ISSN: 2045-2322
Date of First Compliant Deposit: 9 April 2018
Date of Acceptance: 1 March 2018
Last Modified: 11 Apr 2018 19:43
URI: http://orca.cf.ac.uk/id/eprint/110585

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