Oxazolidinone antibiotics such as linezolid have shown significant therapeutic effects in patients with extensively drug-resistant (XDR) tuberculosis (TB) despite modest effects in rodents and no demonstrable early bactericidal activity in human phase 2 trials. We show that monotherapy with either linezolid or AZD5847, a second-generation oxazolidinone, reduced bacterial load at…
New drugs that retain potency against multidrug/extensively drug-resistant strains of Mycobacterium tuberculosis, with the additional benefit of a shortened treatment duration and ease of administration, are urgently needed by tuberculosis (TB) control programs. Efforts to develop this new generation of treatment interventions have been plagued with numerous problems, the most…
We report here a series of five chemically diverse scaffolds that have in vitro activities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc1 complex in Mycobacterium tuberculosis in a strain-dependent manner. Deletion of the cytochrome bd oxidase generated a hypersusceptible mutant in which resistance was acquired by…
New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1). Further, this…
Current tuberculosis (TB) therapies take too long and the regimens are complex and subject to adverse effects and drug-drug interactions with concomitant medications. The emergence of drug-resistant TB strains exacerbates the situation. Drug discovery for TB has resurged in recent years, generating compounds (hits) with varying potential for progression into…
PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the driver of PA-824 in vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT>MIC). In this study,…
There has been renewed interest in alternative strategies to address bottlenecks in antibiotic development. These include the repurposing of approved drugs for use as novel anti-infective agents, or their exploitation as leads in drug repositioning. Such approaches are especially attractive for tuberculosis (TB), a disease which remains a leading cause…
Clofazimine, a member of the riminophenazine class, is one of the few antibiotics that are still active against multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). However, the clinical utility of this agent is limited by its undesirable physicochemical properties and skin pigmentation potential. With the goal of maintaining potent antituberculosis activity while…
