Antivirulence Benzothiophenes Inhibit Intracellular Mycobacterium tuberculosis by Targeting the Sensor Histidine Kinase MprB

Abstract

Pulmonary tuberculosis remains one of the most prevalent and threatening infectious diseases. Classical anti-tubercular therapy targets essential enzymes of the pathogen Mycobacterium tuberculosis (Mtb), thereby suppressing bacterial growth. However, the emergence of drug-resistant strains necessitates alternative therapeutic approaches. Virulence inhibition is a promising strategy that blocks Mtb virulence factors required for survival within host cells. We previously identified a hit compound, BTP15, which protected fibroblasts and THP-1 macrophages from Mtb-induced cell death ex vivo by blocking phagosomal escape through inhibition of the mycobacterial histidine kinase MprB. Due to poor pharmacokinetics, the structure of BTP15 was optimized. New benzothiophene derivatives were screened for MprB inhibition, microsomal stability, toxicity, and ex vivo efficacy in THP-1 and MRC-5 cells. The lead compound, 7a, exhibited favorable pharmacokinetic parameters, showed no toxicity in mice at 250 mg/kg, and prevented Mtb dissemination in an acute mouse model of tuberculosis.