Strain diversity in (Mtb) underlies distinct clinical presentations and outcomes, but the range of drug susceptibility phenotypes among clinical isolates is poorly understood. We aimed to identify drug response patterns in phylogenetically diverse clinical isolates to combination treatment. We selected 13 strains out of 641 drug-sensitive clinical isolates that capture…
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…
(Mtb) remains a leading cause of infectious disease mortality worldwide, largely due to its ability to survive within host macrophages. Despite advances in understanding the environmental pressures Mtb encounters , the genetic requirements for adaptation and survival within the intracellular niche remain incompletely defined. Here, we employed a genome-wide…
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…
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…
