Sensing and response to environmental cues, such as pH and chloride (Cl−), is critical in enabling Mycobacterium tuberculosis (Mtb) colonization of its host. Utilizing a fluorescent reporter Mtb strain in a chemical screen, we have identified compounds that dysregulate Mtb response to high Cl− levels, with a subset of the hits also inhibiting Mtb growth in host macrophages. Structure–activity relationship studies on the hit compound “C6,” or 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole, demonstrated a correlation between compound perturbation of Mtb Cl− response and inhibition of bacterial growth in macrophages. C6 accumulated in both bacterial and host cells, and inhibited Mtb growth in cholesterol media, but not in rich media. Subsequent examination of the Cl− response of Mtb revealed an intriguing link with bacterial growth in cholesterol, with increased transcription of several Cl−-responsive genes in the simultaneous presence of cholesterol and high external Cl− concentration, versus transcript levels observed during exposure to high external Cl− concentration alone. Strikingly, oral administration of C6 was able to inhibit Mtb growth in vivo in a C3HeB/FeJ murine infection model. Our work illustrates how Mtb response to environmental cues can intersect with its metabolism and be exploited in antitubercular drug discovery.

For decades, ibogaine�the main psychoactive alkaloid found in Tabernanthe iboga�has been investigated as a possible treatment for substance use disorders (SUDs) due to its purported ability to interrupt the addictive properties of multiple drugs of abuse. Of the numerous pharmacological actions of ibogaine and its derivatives, the inhibition of α3β4 nicotinic acetylcholine receptors (nAChRs), represents a probable mechanism of action for their apparent antiaddictive activity. In this Perspective, we examine several classes of compounds that have been discovered and developed to target α3β4 nAChRs. Specifically, by focusing on compounds that have proven efficacious in pre-clinical models of drug abuse and have been evaluated clinically, we highlight the promising potential of the α3β4 nAChRs as viable targets to treat a wide array of SUDs. Additionally, we discuss the challenges faced by the existing classes of α3β4 nAChR ligands that must be overcome to develop them into therapeutic treatments.