In the recently concluded REMox-TB trial, two 4-month moxifloxacin-containing regimens did not meet the criteria for noninferiority compared to the current 6-month first-line regimen to treat tuberculosis (TB). Despite the disappointing result, this phase 3 clinical trial provides a rare opportunity to gauge the predictive accuracy of the nonclinical models…
The PLP-dependent transaminase (BioA) of Mycobacterium tuberculosis and other pathogens that catalyzes the second step of biotin biosynthesis is a now well-validated target for antibacterial development. Fragment screening by differential scanning fluorimetry has been performed to discover new chemical scaffolds and promote optimization of existing inhibitors. Calorimetry confirms binding of…
Shortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treated Mycobacterium tuberculosis-infected marmosets with…
The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived…
Modern tuberculosis (TB) chemotherapy is widely viewed as a crowning triumph of anti-infectives research. However, only one new TB drug has entered clinical practice in the past 40 years while drug resistance threatens to further destabilize the pandemic. Here, we review a brief history of TB drug development, focusing on…
Mycobacterium tuberculosis (Mtb) has evolved within the human immune system as both host and reservoir. The study of genes required for its growth and persistence in vivo thus offers linked insights into its pathogenicity and host immunity. Studies of Mtb mutants have implicated metabolic adaptation (consisting of carbon, nitrogen, vitamin,…
Our understanding of the host-pathogen relationship in tuberculosis (TB) can help guide drug discovery in at least two ways. First, the recognition that host immunopathology affects lesional TB drug distribution means that pharmacokinetic evaluation of drug candidates needs to move beyond measurements of drug levels in blood, whole lungs, or…
Tuberculosis (TB) lesions are extremely complex and dynamic. Here, we review the multiple types and fates of pulmonary lesions that form following infection by Mycobacterium tuberculosis and the impact of this spatial and temporal heterogeneity on the bacteria they harbor. The diverse immunopathology of granulomas and cavities generates a plethora…
