New drugs are needed to treat Mycobacterium tuberculosis infection. A large group of researchers from Rutgers Medical School and Hackensack Meridian Health Center for Discovery & Innovation focused on targeting the menaquinone biosynthetic pathway, specifically the MenG enzyme, as a promising therapeutic strategy. MenG is responsible for the final step in menaquinone biosynthesis, catalyzing the methylation of demethylmenaquinone using S-adenosylmethionine, resulting in the formation of menaquinone. They report the evolution of small molecule inhibitors of MenG, focusing on improving the metabolic stability, aqueous solubility, and mouse pharmacokinetic profile of their initial hit compound JSF-2911. They identified two promising analogs, JSF-4536 and JSF-4898, which demonstrated submicromolar MIC values against M. tuberculosis and improved pharmacokinetic properties compared to the initial hit. While JSF-4536 and JSF-4898 did not show significant efficacy as single agents in a mouse model of M. tuberculosis infection, JSF-4898 enhanced the efficacy of the front-line drug rifampicin. They conclude that further efforts to target M. tuberculosis MenG may lead to compounds with demonstrated in vivo efficacy, either alone or in clinically relevant combinations, that could impact the tuberculosis pandemic.
Sharma P, Jiang Q, Li SG, Ocke E, Tsotetsi K, Sukheja P, Singh P, Suryavanshi S, Morrison E, Thadkapally S, Russo R, Penalva-Lopez S, Cangialosi J, Sharma V, Johnson K, Sarathy JP, Nelson AM, Park S, Zimmerman MD, Alland D, Kumar P, Freundlich JS. Evolution of Small Molecule Inhibitors of Mycobacterium tuberculosis Menaquinone Biosynthesis. J Med Chem. 2025 Mar 13;68(5):5774-5803. doi: 10.1021/acs.jmedchem.4c03156. Epub 2025 Mar 4. PMID: 40035499.
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