Tuberculosis (TB) has been a constant global health challenge, particularly in developing countries. While the current anti-TB regimens are mostly effective against drug-susceptible cases, the lingering issue of persister mycobacteria and the rise of drug resistance necessitate the development of shorter treatments that involve drugs with novel modes of action. In recent years, there has been growing interest in targeting the negatively charged mycobacterial membrane due to its pivotal role in viability. Cationic amphiphiles are particularly well-suited for this purpose, and herein we describe our works on cationic quinone-containing small molecules with antimycobacterial activity and ability to redox-cycle. We identified a series of dioxonaphthoimidazoliums which were previously evaluated as antimalarials. Upon extensive study in M. bovis bacillus Calmette-Guérin (BCG) to establish structure-activity relationship (SAR), we found that the positive charge, the quinone group, and substantial lipophilicity are essential to achieving submicromolar inhibitory activity. The potent compounds are bactericidal at micromolar range, highly selective over mammalian cells, and do not show glycerol dependence for activity. The quinone group confers the ability to generate reactive oxygen species (ROS), as confirmed by in vitro and in vivo experiments, as well as induction of the redox-sensing furA promoter. Consistent with this finding, the compounds were inactive under hypoxic conditions but showed bactericidal activity against nutrient-starved mycobacteria, indicating the necessity of oxygen for activity. Further tests revealed that the compounds do not induce the cell envelope stress-induced promoter piniBAC and appear to be ineffective in causing membrane depolarization and permeabilization. Taken together, our findings show a novel class of ROS-generating cationic amphiphiles with promising antimycobacterial activity.

Development of quinone-containing cationic amphiphiles as small molecule antimycobacterials

ACS Spring Meeting 2021

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