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A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis

Abstract

Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually1. Estimates indicate that one-third of the world population is infected with latent M. tuberculosis2. The synergy between tuberculosis and the AIDS epidemic3,4,5, and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary public health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a series of compounds containing a nitroimidazopyran nucleus that possess antitubercular activity. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity against multidrug-resistant M. tuberculosis and promising oral activity in animal infection models. We conclude that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis.

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Figure 1: Structure of Metronidazole, CGI-17341 and PA-824.
Figure 2: NAP activity on static MTB maintained in microaerophilic culture.
Figure 3: In vivo activity of PA-824 in murine and guinea pig models of tuberculosis infection.
Figure 4: Effects of NAP on protein and lipid synthesis.
Figure 5: Metabolism of 14C-labelled PA-824 BCG cells were incubated with labelled drug, and labelled metabolites were recovered from disrupted cells and analysed by TLC.

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Correspondence to C. Kendall Stover.

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Stover, C., Warrener, P., VanDevanter, D. et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405, 962–966 (2000). https://doi.org/10.1038/35016103

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