Microbiological profile, preclinical pharmacokinetics and efficacy of CRS0393, a novel antimycobacterial agent targeting MmpL3

Urs A Ochsner; Mary A De Groote; Thale C Jarvis; Hang Liu; Tessa Youmans; Teresa Hoang; Wendy Ribble; Joshua Day; Wei Li; Camron Pearce; Amanda Walz; Chandra M Panthi; Binayak Rimal; Casey M Stevens; Helen I Zgurskaya; Mary Jackson; Diane Ordway; Mercedes Gonzalez-Juarrero; Xicheng Sun; Gyanu Lamichhane; Clifford Mason

doi:10.1016/j.tube.2022.102288

Microbiological profile, preclinical pharmacokinetics and efficacy of CRS0393, a novel antimycobacterial agent targeting MmpL3

Tuberculosis (Edinb). 2023 Jan:138:102288. doi: 10.1016/j.tube.2022.102288. Epub 2022 Nov 29.

Authors

Urs A Ochsner¹, Mary A De Groote², Thale C Jarvis², Hang Liu², Tessa Youmans², Teresa Hoang², Wendy Ribble², Joshua Day², Wei Li³, Camron Pearce³, Amanda Walz³, Chandra M Panthi⁴, Binayak Rimal⁴, Casey M Stevens⁵, Helen I Zgurskaya⁵, Mary Jackson³, Diane Ordway³, Mercedes Gonzalez-Juarrero³, Xicheng Sun², Gyanu Lamichhane⁴, Clifford Mason²

Affiliations

¹ Crestone, Inc., 6075 Longbow Dr, Boulder, CO, USA. Electronic address: uochsner@crestonepharma.com.
² Crestone, Inc., 6075 Longbow Dr, Boulder, CO, USA.
³ Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, 200 West Lake Street, Colorado State University, Fort Collins, CO, USA.
⁴ Johns Hopkins University, 1550 Orleans Street, Baltimore, MD, USA.
⁵ University of Oklahoma, Department of Chemistry and Biochemistry, 101 Stephenson Parkway, Norman, OK, USA.

Abstract

The benzothiazole amide CRS0393 demonstrated excellent in vitro activity against nontuberculous mycobacteria (NTM), including M. abscessus isolates from cystic fibrosis (CF) patients, with minimum inhibitory concentrations (MICs) of ≤0.03-0.5 μg/mL. The essential transport protein MmpL3 was confirmed as the target via analysis of spontaneous resistant mutants and further biological profiling. In mouse pharmacokinetic studies, intratracheal instillation of a single dose of CRS0393 resulted in high concentrations of drug in epithelial lining fluid (ELF) and lung tissue, which remained above the M. abscessus MIC for at least 9 hours post-dose. This exposure resulted in a penetration ratio of 261 for ELF and 54 for lung tissue relative to plasma. CRS0393 showed good oral bioavailability, particularly when formulated in kolliphor oil, with a lung-to-plasma penetration ratio ranging from 0.5 to 4. CRS0393 demonstrated concentration-dependent reduction of intracellular M. abscessus in a THP-1 macrophage infection model. CRS0393 was well tolerated following intranasal administration (8 mg/kg) or oral dosing (25 mg/kg) once daily for 28 days in dexamethasone-treated C3HeB/FeJ mice. Efficacy against M. abscessus strain 103 was achieved via the intranasal route, while oral dosing will need further optimization. CRS0393 holds promise for development as a novel agent with broad antimycobacterial activity.

Keywords: Antibacterial; Efficacy; MmpL3; NTM; Pharmacokinetics; Tuberculosis.

Publication types

Letter
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology
Anti-Bacterial Agents / therapeutic use
Cystic Fibrosis* / drug therapy
Cystic Fibrosis* / microbiology
Lung
Mice
Microbial Sensitivity Tests
Mycobacterium Infections, Nontuberculous* / drug therapy
Mycobacterium Infections, Nontuberculous* / microbiology
Mycobacterium tuberculosis*
Nontuberculous Mycobacteria

Substances

Anti-Bacterial Agents

Grants and funding

R01 AI116525/AI/NIAID NIH HHS/United States