Grant: Project Grant - PA: Antimicrobial Resistance (Bridge Grant)

Prior to Covid-19 pandemic, Tuberculosis (TB) had the notorious distinction of causing the highest number of deaths every year, amongst infectious diseases. In 2021, approximately 10 million people developed TB and 1.5 million lives were lost to the disease. Unfortunately, such a high burden of TB disease still exists in spite of the fact that TB is curable and drugs targeting Mycobacterium tuberculosis (the causative agent of TB) have been around since the 1940s. A significant hindrance to TB control and eradication is the prolonged treatment regimen. Patients who develop TB are treated with 2-4 drugs over a period of 6 months. This is extremely challenging in terms of implementation and often leads to non-compliance, treatment failure and development of drug resistance. These lengthy regimens are necessitated due to the ability of M. tuberculosis to persist and survive against high concentrations of antibiotics. These surviving subpopulations of cells are not resistant to the antibiotics but exhibit tolerance to the antibiotics and are referred to as persisters. Previous studies, including from our lab, have shown that the TB bacteria in the host are extremely diverse and heterogeneous. This heterogeneity is what drives the development of drug- tolerant subpopulations. In this study, we propose to characterize the physiological states and phenotypic heterogeneity in persisting mycobacterial subpopulations during infection. These studies will not only lead to identification of novel targets for drug discovery but understanding the physiology of these persisters will aid in design of faster and more effective therapeutic regimens.