Multiple studies have reported genes in the M. tuberculosis (Mtb) genome that are under diversifying selection, based on genetic variants among Mtb clinical isolates. These might reflect adaptions to selection pressures associated with modern clinical treatment of TB. Many, but not all, of these genes under selection are related to…
Understanding the functional impact of bacterial genetic diversity is crucial for linking pathogen variants to clinical outcomes. Here, we introduce a high-throughput cytological profiling pipeline optimized for (Mtb) clinical strains, integrating OD-calibrated feature analysis and high-content microscopy. Our system quantifies single-bacterium morphological and physiological traits related to DNA replication, redox…
A key challenge in preclinical tuberculosis drug development is identifying optimal antibiotic combinations. Drug interactions are complex because one drug may affect () physiology in a way that alters the activity of another drug. Conventional pharmacodynamic evaluation based on colony-forming units (CFU) does not provide information about this physiologic interaction…
Tuberculosis (TB) remains the foremost cause of death from infectious diseases globally, prompting ongoing efforts to improve treatment options. This includes developing compounds with novel modes of action and identifying optimal treatment regimens that allow for treatment shortening. One promising strategy involves targeting cytochrome bc oxidase in Mycobacterium tuberculosis, a…
Africa’s vast genetic diversity poses challenges for optimising drug treatments in the continent, which is exacerbated by the fact that drug discovery and development efforts have historically been performed outside Africa. This has led to suboptimal therapeutic outcomes in African populations and overall scarcity of relevant pharmacogenetic data, including characteristic…
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),…
