A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis
Top Cited Papers
- 1 June 2000
- journal article
- letter
- Published by Springer Nature in Nature
- Vol. 405 (6789), 962-966
- https://doi.org/10.1038/35016103
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.Keywords
This publication has 25 references indexed in Scilit:
- The effect of oxygenated mycolic acid composition on cell wall function and macrophage growth in Mycobacterium tuberculosisMolecular Microbiology, 1998
- Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequenceNature, 1998
- The Evolving Relation between Humans andMycobacterium tuberculosisNew England Journal of Medicine, 1998
- Tubercolosis: a neglected disease strikes backTrends in Microbiology, 1993
- Tuberculosis: Commentary on a Reemergent KillerScience, 1992
- A guinea pig model of experimental airborne tuberculosis for evaluation of the response to chemotherapy: the effect on bacilli in the initial phase of treatmentTubercle, 1991
- Nitroimidazoles XXI 2,3-dihydro-6-nitroimidazo [2,1-b] oxazoles with antitubercular activity,European Journal of Medicinal Chemistry, 1989
- Structural alterations that differentially affect the mutagenic and antitrichomonal activities of 5-nitroimidazolesJournal of Medicinal Chemistry, 1987
- Potential radiosensitizing agents. DinitroimidazolesJournal of Medicinal Chemistry, 1979
- Mechanism of antimicrobial action of metronidazoleJournal of Antimicrobial Chemotherapy, 1979