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

C. Kendall Stover, Paul Warrener, Donald R. VanDevanter, David R. Sherman, Taraq M. Arain, Michael H. Langhorne, Scott W. Anderson, J. Andrew Towell, Ying Yuan, David N. McMurray, Barry N. Kreiswirth, Clifton E. Barry, William R. Baker

Research output: Contribution to journalArticlepeer-review

867 Scopus citations

Abstract

Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually. Estimates indicate that one-third of the world population is infected with latent M. tuberculosis. The synergy between tuberculosis and the AIDS epidemic, 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 PA824 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.

Original languageEnglish (US)
Pages (from-to)962-966
Number of pages5
JournalNature
Volume405
Issue number6789
DOIs
StatePublished - Jun 22 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

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