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 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 PA-824 showed potent bactericidal activity against multidrugresistant 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.

Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations

“…4A). PA-824 (pretomanid), a drug showing promise in clinical trials (26,27), minimally impacted 2 wk-starved Mtb at doses at or below 5.5 μM and did not create DD Mtb under those conditions (Fig. 4B).…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…They have two mechanisms of action-the inhibition of mycolic acid (mycobacterial cell wall) synthesis and the liberation of toxic nitric oxide within M tuberculosis. 369,370 These drugs act against actively dividing and non-replicating bacilli and show potent sterilising activity in mouse models.…”

“…371 Spontaneous mutations conferring resistance to delamanid are relatively frequent, occurring in approximately one in 100 000 to 1 000 000 bacilli. 369,[372][373][374] In human beings, delamanid is highly protein bound (>99·5%), is metabolised by albumin, 375 has a half-life of 34 h, and its DM-6705 metabolite has a half-life of more than 150 h. 375 Delamanid has low oral bioavailability, so it has to be given with food, and dosing must be separated in time from dosing of other medications. Co-administration with ritonavirboosted protease inhibitors or efavirenz does not markedly affect delamanid exposure.…”

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

“…The novel TB drugs currently in clinical trials were not discovered through target-based cell screening but through either whole-cell phenotypic screening (TMC207 [1]) or chemical modification of previous hits (PA-824 [35], SQ109 [12], and OPC-67683 [28]). The advantage of target-based chemical library screening is that the target of the identified inhibitors is known, which means that the mode of action and mode of resistance can be easily identified.…”