Development of novel agents to eliminate TB persisters

ABSTRACT Therapy for tuberculosis (TB) is an enigma of ineffectiveness. Despite prolonged treatment times, about 5% of TB patients endure poor outcomes, including treatment failure or relapse. Implicated in these failures is the presence of drug-tolerant Mycobacterium tuberculosis (Mtb) subpopulations, also known as "persisters". In an effort to eliminate these bacilli, we developed a drug screening assay targeting Mtb persister cells that survive high concentrations of two front-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF). We found that netupitant (NTP), an FDA-approved oral antiemetic drug with a good safety profile, prevented the regrowth of INH/RIF persisters. We then showed that NTP enhanced the bactericidal activity of a broad spectrum of anti- TB drugs and had excellent activity in other models of Mtb bacteriostasis. Here we seek to assess the potential of NTP for TB drug development. We will adopt molecular genetic and biochemical strategies to define the mechanism of NTP action and resistance on persister bacilli. We will also test the ability of NTP to improve outcomes in a mouse model of TB treatment and relapse. Altogether this study will assess the potential for advancing NTP as a novel anti-persister agent, and enhance our understanding of Mtb persister biology, furthering the important goal of reducing TB treatment duration and improving outcomes.