In the fight against tuberculosis (TB), the lingering issue of persister Mycobacteria and the rise of drug resistance necessitate development of novel treatments. There has been growing interest in targeting mycobacterial energetics due to its pivotal role in bacterial viability. Through extensive structure-activity relationship studies and various biological assays, we identified two classes of cationic naphthoquinoneimidazoles with potent antimycobacterial activity but contrasting modes of action that perturb mycobacterial energetics. First, we developed a series of dioxonaphthoimidazoliums (1), whose positive charge activates the quinone group in the scaffold to generate reactive oxygen species (ROS) upon reduction by the mycobacterial type II NADH dehydrogenase (NDH-2). The second series is a library of naphthoquinoneimidazoles with a distal positive charge on a trialkylphosphonium moiety (2), which showed diminished capacity for ROS generation but rapid membrane depolarization, resulting in depletion of intracellular ATP. The active compounds from both series exhibited bactericidal activity against M. tuberculosis H37Rv at low micromolar range and highly selective over mammalian cells. Taken together, our findings show novel classes of cationic small molecules with promising antimycobacterial activity.

Development of cationic naphthoquinoneimidazoles as novel antimycobacterial agents

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ACS Fall 2022

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