Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid metabolism regulator.

Successful colonization of the host requires Mycobacterium tuberculosis (Mtb) to sense and respond coordinately to disparate environmental cues during infection and adapt its physiology. However, how Mtb response to environmental cues and the availability of key carbon sources may be integrated is poorly understood. Here, by exploiting a reporter-based genetic screen, we have unexpectedly found that overexpression of transcription factors involved in Mtb lipid metabolism altered the dampening effect of low environmental potassium concentrations ([K+]) on the pH response of Mtb.

response to cholesterol is integrated with environmental pH and potassium levels via a lipid utilization regulator.

How bacterial response to environmental cues and nutritional sources may be integrated in enabling host colonization is poorly understood. Exploiting a reporter-based screen, we discovered that overexpression of (Mtb) lipid utilization regulators altered Mtb acidic pH response dampening by low environmental potassium (K). Transcriptional analyses unveiled amplification of Mtb response to acidic pH in the presence of cholesterol, a major carbon source for Mtb during infection, and vice versa.

Rv0500A is a transcription factor that links Mycobacterium tuberculosis environmental response with division and impacts host colonization.

For Mycobacterium tuberculosis (Mtb) to successfully infect a host, it must be able to adapt to changes in its microenvironment, including variations in ionic signals such as pH and chloride (Cl ), and link these responses to its growth. Transcriptional changes are a key mechanism for Mtb environmental adaptation, and we identify here Rv0500A as a novel transcriptional regulator that links Mtb environmental response and division processes. Global transcriptional profiling revealed that Rv0500A acts as a repressor and influences the expression of genes related to division, with the magnitude of its effect modulated by pH and Cl .

Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs.

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.

Potassium response and homeostasis in Mycobacterium tuberculosis modulates environmental adaptation and is important for host colonization.

Successful host colonization by bacteria requires sensing and response to the local ionic milieu, and coordination of responses with the maintenance of ionic homeostasis in the face of changing conditions. We previously discovered that Mycobacterium tuberculosis (Mtb) responds synergistically to chloride (Cl-) and pH, as cues to the immune status of its host. This raised the intriguing concept of abundant ions as important environmental signals, and we have now uncovered potassium (K+) as an ion that can significantly impact colonization by Mtb.

Fluorescent Mycobacterium tuberculosis reporters: illuminating host-pathogen interactions.

The pathogenesis of Mycobacterium tuberculosis (Mtb) is intrinsically linked to its intimate and enduring interaction with its host, and understanding Mtb-host interactions at a molecular level is critical to attempts to decrease the significant burden of tuberculosis disease. The marked heterogeneity that exists in lesion progression and outcome during Mtb infection necessitates the development of methods that enable in situ analyses of Mtb biology and host response within the spatial context of tissue structure. Fluorescent reporter Mtb strains have thus come to the forefront as an approach with broad utility for the study of the Mtb-host interface, enabling visualization of the bacteria during infection, and contributing to the discovery of several facets such as non-uniformity in microenvironments and Mtb physiology in vivo, and their relation to the host immune response or therapeutic intervention.