The bedaquiline, pretomanid, and linezolid (BPaL) regimen has shown significant efficacy in treating patients with multidrug-resistant and extensively drug-resistant tuberculosis. This study assessed whether delamanid, a closely related nitroimidazole, could replace pretomanid in the BPaL regimen by directly comparing the efficacy of bedaquiline, delamanid, and linezolid (BDL) and BPaL regimens…
Tuberculosis (TB) chemotherapy was once considered a crowning triumph of modern medicine but has since reemerged as a persisting paradox. While therapeutically still effective in most cases, current frontline treatments for TB remain largely unchanged from their introduction over 50 years ago and continue to require a minimum of 6…
Despite the approval of two first-in-class anti-tuberculars over the past two decades, the global burden of tuberculosis (TB) remains unacceptably high, in part due to the emergence and spread of drug-resistant strains of Mycobacterium tuberculosis (Mtb). This review summarizes advances and ongoing challenges in anti-TB drug discovery, focusing on identifying…
Post-antibiotic effect (PAE) describes the delay in bacterial growth that continues after antibiotics are cleared. The physiologic basis of PAE in Mycobacterium tuberculosis (Mtb) remains poorly understood. Here, we evaluated the long-standing hypothesis that PAE reflects the time required for bacteria to recover from drug-induced physiologic damage by comparing Mtb…
The human pathogen Mycobacterium tuberculosis (Mtb) thrives in lipid-rich microenvironments. A strong body of evidence demonstrated that, during infection, Mtb utilizes long-chain fatty acids (LCFA) as a preferred carbon source. However, LCFA also have antimicrobial properties. Mtb must therefore employ mechanisms to utilize LCFA while mitigating their toxicity. Using transposon…
Controlled human infection models (CHIMs) can accelerate vaccine development for infectious diseases. Mycobacterium tuberculosis is a human-adapted pathogen that is the leading infectious cause of death worldwide. M tuberculosis infection results in a spectrum of clinical outcomes that are incompletely modelled in animals. To date, the risks of infection, prolonged…
Linezolid, an oxazolidinone, is a cornerstone of treatment regimens for highly drug-resistant tuberculosis but cannot be used in drug-susceptible disease because of toxicity. This toxicity results from inhibition of mammalian mitochondrial protein synthesis. Here we show the development of a new oxazolidinone, MK-7762, with antitubercular activity that is better than…
Tuberculosis (TB) remains a leading cause of death due to an infectious agent. Adherence to long and complex TB treatments is supported by methods including directly observed therapy. The negative impact of missed drug doses on clinical outcomes is well established, highlighting both the importance of adherence support and methods…
