Understanding resistance and tolerance to nitroimidazoles in Mycobacterium tuberculosis

Killing ~1.5 million people annually, tuberculosis (TB) remains a leading cause of death due to bacterial infections worldwide. A vaccine preventing TB in adults has yet to be developed. Control of TB thus largely depends on chemotherapy, which requires months of treatment with several drugs. Pretomanid (Pa) and delamanid (DLM) are novel nitroimidazoles that were approved for treatment of drug-resistant (DR) TB in 2014 and 2019, respectively. Combining Pa with bedaquiline (B) and linezolid (L) established to the so-called BPaL regimen, which drastically shortened treatment duration for DR-TB. Several subsequent clinical trials have confirmed the treatment shortening activity of Pa-containing regimens. Pa and DLM can kill replicating and non-replicating Mycobacterium tuberculosis (Mtb) by similar, complex mechanisms of action (MOAs) that are only partially understood. Here we propose to apply innovative genome-wide screens to identify the Mtb genes determining Pa/DLM potency in vitro and during infection. In preliminary work we identified Mtb’s major intrinsic resistance determinant for Pa/DLM, which we will analyze mechanistically using both biochemical, metabolomic and genetic techniques. Finally, we will exploit Pa’s dual mechanism of action to determine the impact of Mtb’s intrinsic Pa resistance and intrinsic Pa tolerance on treatment duration. The proposed research will be executed by a team combining expertise in mycobacterial genetics, genomics, metabolism, metabolomics and animal models with the goal to advance our understanding of Pa/DLM’s MOA, enable development of more potent nitroimidazoles and guide the design of shorter TB treatment regimens.