Identifying the Determinants of Persister Cell Survival in M. tuberculosis.

PROJECT SUMMARY / ABSTRACT Mycobacterium tuberculosis (Mtb) remains a threat to human health, and treatment of tuberculosis (TB) is arduous, requiring multiple, potentially toxic antibiotics administered for 4 months or more. Thus, there remains a critical need to understand the mechanisms enabling Mtb to survive prolonged exposure to lethal antibiotics. Mtb, like many bacteria, has the ability to form antibiotic persister cells ,which can survive for prolonged when exposed to bactericidal antibiotics. The goal of this proposal is to apply a combination of genetic and proteomic approaches to identify the key pathways enabling the survival of antibiotic persister cells in Mtb. In Aim 1 we propose to rigorously identify the genetic determinants of persister cells to identify genes needed for persister cell formation in multiple contexts, enabling an identification of core pathways contributing to persistence across multiple contexts. In Aim 2 we will use proteomics to define the signaling events associated with persister formation which will help both to prioritize factors studied in vivo, and to form clear biochemical hypotheses. If successful, these studies would provide insights that could be leveraged therapeutically to develop “persistence inhibitors” that act cooperatively with traditional antibiotics to hasten Mtb eradication in patients.