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Review
. 2017 Sep;25(9):756-767.
doi: 10.1016/j.tim.2017.05.007. Epub 2017 Jun 13.

Antimycobacterial Metabolism: Illuminating Mycobacterium tuberculosis Biology and Drug Discovery

Divya Awasthi  1 , Joel S Freundlich  2
Affiliations
Review

Antimycobacterial Metabolism: Illuminating Mycobacterium tuberculosis Biology and Drug Discovery

Divya Awasthi et al. Trends Microbiol. 2017 Sep.

Abstract

Bacteria are capable of performing a number of biotransformations that may activate or deactivate xenobiotics. Recent efforts have utilized metabolomics techniques to study the fate of small-molecule antibacterials within the targeted organism. Examples involving Mycobacterium tuberculosis are reviewed and analyzed with regard to the insights they provide as to both activation and deactivation of the antibacterial. The studies, in particular, shed light on biosynthetic transformations performed by M. tuberculosis while suggesting avenues for the evolution of chemical tools, highlighting potential areas for drug discovery, and mechanisms of approved drugs. A two-pronged approach investigating the metabolism of antibacterials within both the host and bacterium is outlined and will be of value to both the chemical biology and drug discovery fields.

Keywords: antibacterial; biotransformation; metabolism; metabolomics; small molecule; tuberculosis.

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Figures

Figure 1
Figure 1
Ester Hydrolysis. Targeted metabolomic analysis of M. tuberculosis treated with NTZ showed dose–dependent accumulation of the compound and partial conversion to TIZ [38].
Figure 2
Figure 2
Chemical Structures of WR-99210 and Methotrexate Analogs, JSF-1187 and JSF-1183. These accumulate inside M. tuberculosis in a dose–dependent manner as confirmed by metabolomics [43].
Figure 3
Figure 3
A) Ester Hydrolysis of CD117 Affords JSF-2000. While metabolomics analysis showed M. tuberculosis uptake of both CD117 and JSF-2000, CD117 is partially hydrolyzed to JSF-2000 inside the bacterium. B) Two CD117 analogs with improved metabolic stability are JSF-2070 and JSF-2088 [21].
Figure 4
Figure 4
N–methylation of Compound 14 [47].
Figure 5
Figure 5
Amine Metabolism with Antifolates. A) Biotransformation of PAS, sulfanilamide, sulfamethoxazole and dapsone in M. tuberculosis. B) Metabolomics analysis showed concentration–dependent formation of PAS–derived Ia & IIa and N–methyl PAS Ib & IIb after exposure of M. tuberculosis to PAS for 18 h [53].
Figure 6
Figure 6
Metabolism of PA-824 [64].
See this image and copyright information in PMC

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