Identification of Quinoline-Based Mmpl3 Inhibitors against Mycobacterium Tuberculosis Using Antimicrobial Screening, Docking and Molecular Dynamics Simulation

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a severe global health issue, exacerbated by the emergence of drug-resistant strains. The rise of multi-drug resistant (MDR) and extensively drug-resistant (XDR) TB strains, which are unresponsive to conventional anti-TB drugs, significantly increases the mortality rate associated with the disease. The primary factors contributing to drug resistance include genetic mutations in Mtb, misuse of antibiotics, and the use of broad-spectrum antibiotics. In 2019, the World Health Organization reported approximately 10 million TB cases and 1.2 million TB-related deaths worldwide. Of these cases, nearly 500,000 were rifampicin-resistant TB (RR-TB), with 78% being MDR-TB. High MDR-TB rates were noted particularly in India, China, and the Russian Federation.

The complex cell wall of Mtb, comprised of peptidoglycan, arabinogalactan, and mycolic acids, is critical for its pathogenicity and poses a significant challenge for drug penetration. Mycobacterial Membrane Protein Large 3 (MmpL3), an essential inner membrane transporter, is responsible for exporting trehalose monomycolate (TMM), a precursor for mycolic acid and trehalose dimycolate (TDM) synthesis. Given its crucial role in Mtb’s cell wall biosynthesis, MmpL3 represents a promising target for new anti-TB drugs.

The review highlights that targeting MmpL3 through various scaffolds like adamantyl, pyrrole, and indole carboxamide derivatives is a promising strategy for developing new anti-TB therapies. While many of these compounds show potential, challenges such as solubility, toxicity, and plasma protein binding remain.