Efforts to develop effective and safe drugs for treatment of tuberculosis require preclinical evaluation in animal models. Alongside efficacy testing of novel therapies, effects on pulmonary pathology and disease progression are monitored by using histopathology images from these infected animals. To compare the severity of disease across treatment cohorts, pathologists…
Tuberculosis (TB) treatment is lengthy and complicated and patients often develop chronic lung disease. Recent attention has focused on host-directed therapies aimed at optimizing immune responses to Mycobacterium tuberculosis (Mtb), as adjunctive treatment given with antitubercular drugs. In addition to their cholesterol-lowering properties, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have…
Prevention of pulmonary tuberculosis by vaccination has proven an elusive goal. In a recent study, Darrah et al. show that prevention of infection and disease can be achieved in non-human primates by intravenous administration of the century-old vaccine BCG. This finding heralds a step-change in the approach to TB vaccine development.
: Tuberculosis is the leading cause of death from infectious disease. Current drug therapy requires a combination of antibiotics taken over >6 months. An urgent need for new agents that can shorten therapy is required. In order to develop new drugs, simple assays are required that can identify efficacious compounds rapidly…
The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with…
Inclusion of pyrazinamide (PZA) in the tuberculosis (TB) drug regimen during the 1970s enabled a reduction in treatment duration from 12 to 6 months. PZA has this remarkable effect in patients despite displaying poor potency against Mycobacterium tuberculosis (Mtb) in vitro. The pharmacological basis for the in vivo sterilizing activity of the drug…
The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and…
Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculous meningitis (TBM) specifically are nearly uniformly fatal, with little information being available to guide the treatment of these patients. Delamanid (DLM), a nitro-dihydro-imidazooxazole, is a new, well-tolerated anti-TB drug with a low…
