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. 2024 Jan 11;12(1):e0367723.
doi: 10.1128/spectrum.03677-23. Epub 2023 Dec 11.

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

John T Williams  1 , Matthew Giletto  2 , Elizabeth R Haiderer  1 , Bilal Aleiwi  2 , Teresa Krieger-Burke  2 , Edmund Ellsworth  2 , Robert B Abramovitch  1
Affiliations

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

John T Williams et al. Microbiol Spectr. .

Abstract

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.

Keywords: MmpL3; Mycobacterium tuberculosis; drug development; nontuberculous mycobacteria.

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Conflict of interest statement

R.B.A. and E.E. are owners of Tarn Biosciences, Inc., a company that is working to develop new antimycobacterial drugs. R.B.A., J.T.W., and E.E. are inventors on a patent application covering matter described in this study.

Figures

Fig 1
Fig 1
Structure-activity relationship studies enhance potency of several HC2099 analogs against Mtb. (A–D) Structures and activity of HC2099 (A) analogs MSU-43085 (B), MSU-43165 (C), and MSU-43170 (D). Corresponding inhibitor descriptors for dose-response curves (E) are included as the hillslope, EC50, and EC90. The dose-response curves for each inhibitor (E) are compared to parent compound HC2099 (black). Dose-response curves were run in triplicate; error bars indicate the S.D. of the mean.
Fig 2
Fig 2
In vivo activity of prioritized HC2099 analogs against Mtb. (A) Bacterial lung burden (CFU/mL + 1) of C57Bl/6 mice following an acute (2 week) infection with Mtb Erdman and treated with vehicle (corn oil), INH (25 mg/kg), MSU-43085 (200 mg/kg), or MSU-43165 (200 mg/kg). Dotted line indicates the limit of detection (20 CFUs). CFU/mL data were +1 transformed to visualize 0 CFU data on a log scale. Solid black lines indicate the median bacterial infection in each group. Groups were compared using a two-way ANOVA. **P < 0.005, ****P < 0.0001.
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