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Antimicrobial resistance (AMR) is one of the world’s top health challenges. Mycobacterium tuberculosis (Mtb), the single leading cause of death from infectious disease, may cause the greatest number of infections characterized by AMR and is becoming progressively incurable. The most familiar form of AMR is heritable, but non-heritable AMR—phenotypic tolerance—is one of the major factors that make tuberculosis difficult to treat. My lab is taking three routes to search for compounds active against Mtb in states in which it is phenotypically tolerant to most TB drugs: whole cell screening under non-replicating conditions; target-based screening against enzymes that Mtb needs to survive under stresses that block its replication; and testing active agents from those screens against Mtb in a state where it can no longer form colonies on solid media, yet retains the potential to cause disease.