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

Article Details

Citation
Copy to clipboard

Baptista R, Fazakerley DM, Beckmann M, Baillie L, Mur LAJ

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

Sci Rep. 2018 Mar 23;8(1):5084. doi: 10.1038/s41598-018-23110-1.

PubMed ID
29572459 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drugs