ArticlePLoS biology2021
Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs.
Article in PLoS biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
11 citing papers in PubMed, 21 citations in OpenAlex.
- The Quantification of Drug Accumulation within Gram-Negative Bacteria.ACS infectious diseases · 2026Article
- DifferentiatingInfection and immunity · 2025Article
- Cholesterol metabolism and intrabacterial potassium homeostasis are intrinsically related in Mycobacterium tuberculosis.PLoS pathogens · 2025Article
- Building Spatiotemporal Understanding ofACS infectious diseases · 2025Review
- Identification and optimization of pyridine carboxamide-based scaffold as a drug lead forAntimicrobial agents and chemotherapy · 2024Article
- Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid metabolism regulator.PLoS genetics · 2024Article
- Shining a light on bacterial environmental cue integration and its relation to metabolism.Molecular microbiology · 2023Article
- PrrA modulates Mycobacterium tuberculosis response to multiple environmental cues and is critically regulated by serine/threonine protein kinases.PLoS genetics · 2022Article
- Article
- Rv0500A is a transcription factor that links Mycobacterium tuberculosis environmental response with division and impacts host colonization.Molecular microbiology · 2022Article
- Spatial relationships of intra-lesion heterogeneity in Mycobacterium tuberculosis microenvironment, replication status, and drug efficacy.PLoS pathogens · 2022Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
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