Tuberculosis, a persistent public health challenge worldwide, is transmitted when exhaled (Mtb) particles expelled from an infected individual are inhaled by a susceptible person. To study the adaptation of Mtb during transition between hosts, we developed a transmission simulation system (TSS) that combines controlled pathogen aerosolization and measurement of bioaerosol…
Cavitary tuberculosis is difficult to cure and constitutes a site of relapse. Bedaquiline has been a wonder drug in the treatment of multidrug-resistant tuberculosis, but emergence of resistance threatens the sustainability of its success. We designed site-of-disease pharmacokinetic studies to spatially resolve the penetration of bedaquiline, and 2 next-generation diarylquinolines,…
Treatments for tuberculosis remain lengthy, motivating a search for new drugs with novel mechanisms of action. However, it remains challenging to determine the direct targets of a drug and which disrupted cellular processes lead to bacterial killing. We developed a computational tool, DECIPHAER (decoding cross-modal information of pharmacologies via autoencoders),…
Tuberculosis remains the leading cause of death from an infectious disease. Here we report the discovery of a first-in-class small-molecule inhibitor targeting PurF, the first enzyme in the mycobacterial de novo purine biosynthesis pathway. The lead candidate, JNJ-6640, exhibited nanomolar bactericidal activity in vitro. Comprehensive genetic and biochemical approaches confirmed…
There is currently a public health crisis due to the rise of multidrug-resistant tuberculosis cases, as well as the rise in the number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported…
Tuberculosis (TB) continues to pose a global public health threat, exacerbated by rising drug-resistant strains of (Mtb). DacB1, a D,D-carboxypeptidase critical in Mtb peptidoglycan biosynthesis, is a promising target for β-lactam antibiotics (BLs), which remain underutilized in TB treatment. Dual BL therapy may enhance efficacy by inactivating multiple targets within…
Establishing efficacy benchmarks in preclinical tuberculosis (TB) models is essential for optimizing and prioritizing therapeutic regimens. However, standardized classification methods for comparing high-performing regimens are currently lacking. This study defines a quantitative framework utilizing rifampicin-based regimens in a high-burden aerosol BALB/c mouse model, incorporating both male and female mice to…
In the absence of effective patient-stratification approaches, tuberculosis (TB) treatment relies on overtreating most patients to ensure high cure rates. Shortening treatment duration without compromising efficacy is therefore high on the agenda of the global TB community. While new and better drugs are certainly needed, we argue that innovative but…
