The Mycobacterium tuberculosis MmpL3 inhibitor MSU-43085 is active in a mouse model of infection

Abstract

Addressing drug resistance in Mycobacterium tuberculosis (Mtb) requires the development of new drugs with new targets. We previously identified 13 MmpL3 inhibitors from a screen of a small library of Mtb growth inhibitors. In this report, we describe the biological activities of a set of HC2099 analogs active against Mtb in vitro , intracellular Mtb, as well as M. abscessus and M. avium . Pharmacokinetic (PK) studies identified MSU-43085 as orally bioavailable with a short half-life. High dosing (100 mg/kg) saturates clearance processes, enabling efficacy studies. The results of an in vivo efficacy study found that MSU-43085 was active against Mtb in an acute murine TB infection model but lacked activity in a chronic murine TB infection model. The results of this study serve as a proof of concept for this series and support further optimizations of the HC2099 series of MmpL3 inhibitors. IMPORTANCE MmpL3 is a protein that is required for the survival of bacteria that cause tuberculosis (TB) and nontuberculous mycobacterial (NTM) infections. This report describes the discovery and characterization of a new small molecule, MSU-43085, that targets MmpL3 and is a potent inhibitor of Mycobacterium tuberculosis (Mtb) and M. abscessus survival. MSU-43085 is shown to be orally bioavailable and efficacious in an acute model of Mtb infection. However, the analog is inactive against Mtb in chronically infected mice. Pharmacokinetic and metabolite identification studies identified in vivo metabolism of MSU-43085, leading to a short half-life in treated mice. These proof-of-concept studies will guide further development of the MSU-43085 series for the treatment of TB or NTM infections.