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The carbonic anhydrase inhibitor ethoxzolamide inhibits the Mycobacterium tuberculosis PhoPR regulon and Esx-1 secretion and attenuates virulence

ABSTRACT: The purpose of this study was to examine how ethoxzolamide modulates gene M. tuberculosis gene expression at acidic pH. We observed that ethoxzolamide downregulates genes of the PhoPR regulon.

ORGANISM(S): Mycobacterium tuberculosis

PROVIDER: GSE63917 | GEO | 2015/05/20

SECONDARY ACCESSION(S): PRJNA269492

REPOSITORIES: GEO

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The carbonic anhydrase inhibitor ethoxzolamide inhibits the Mycobacterium tuberculosis PhoPR regulon and Esx-1 secretion and attenuates virulence

Project description:The purpose of this study was to examine how ethoxzolamide modulates gene M. tuberculosis gene expression at acidic pH. We observed that ethoxzolamide downregulates genes of the PhoPR regulon. Mtb strain CDC1551 was grown at 37C in T-25 vented, standing tissue culture flasks in 8 ml of buffered 7H9 medium seeded an initial OD of 0.2. Three conditions were examined with two biological replicates: 1) DMSO treated, pH 7.0, 2) DMSO treated, pH 5.7, 3) 40 µM ethoxzolamide treated, pH 5.7. The CDC1551(phoP::Tn) mutant was grown in a similar manner and treated with DMSO at pH 7.0 and 5.7. Following six days incubation, total bacterial RNA was extracted and analyzed as previously described.

2015-05-20 | E-GEOD-63917 | biostudies-arrayexpress

The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence.

Project description:Mycobacterium tuberculosis must sense and adapt to host environmental cues to establish and maintain an infection. The two-component regulatory system PhoPR plays a central role in sensing and responding to acidic pH within the macrophage and is required for M. tuberculosis intracellular replication and growth in vivo. Therefore, the isolation of compounds that inhibit PhoPR-dependent adaptation may identify new antivirulence therapies to treat tuberculosis. Here, we report that the carbonic anhydrase inhibitor ethoxzolamide inhibits the PhoPR regulon and reduces pathogen virulence. We show that treatment of M. tuberculosis with ethoxzolamide recapitulates phoPR mutant phenotypes, including downregulation of the core PhoPR regulon, altered accumulation of virulence-associated lipids, and inhibition of Esx-1 protein secretion. Quantitative single-cell imaging of a PhoPR-dependent fluorescent reporter strain demonstrates that ethoxzolamide inhibits PhoPR-regulated genes in infected macrophages and mouse lungs. Moreover, ethoxzolamide reduces M. tuberculosis growth in both macrophages and infected mice. Ethoxzolamide inhibits M. tuberculosis carbonic anhydrase activity, supporting a previously unrecognized link between carbonic anhydrase activity and PhoPR signaling. We propose that ethoxzolamide may be pursued as a new class of antivirulence therapy that functions by modulating expression of the PhoPR regulon and Esx-1-dependent virulence.

| S-EPMC4505220 | biostudies-literature

Mycobacterium avium subsp. paratuberculosis K-10 & phoPR comparison

Project description:To compare the transcriptional profile of K-10 and phoPR in the log phase, and to find out the effects of phoPR on MAP gene expression.

2016-03-01 | GSE71291 | GEO

Mycobacterium avium subsp. paratuberculosis K-10 & phoPR comparison

Project description:To compare the transcriptional profile of K-10 and phoPR in the log phase, and to find out the effects of phoPR on MAP gene expression. There are three replicates from K-10 as the control samples, and three replicates from phoPR used to examine the differences.

2016-03-01 | E-GEOD-71291 | biostudies-arrayexpress

Evolutionary conserved mutations in PhoPR attenuate the virulence of animal-adapted tuberculosis strains for humans

2014-07-07 | GSE54421 | GEO

Carbonic anhydrase inhibitor attenuates ischemia-reperfusion induced acute lung injury.

Project description:Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions including lung transplantation, cardiopulmonary bypass surgery, re-expansion of collapsed lung from pneumothorax or pleural effusion and etc. IR-induced ALI remains a challenge in the current treatment. Carbonic anhydrase has important physiological function and influences on transport of CO2. Some investigators suggest that CO2 influences lung injury. Therefore, carbonic anhydrase should have the role in ALI. This study was undertaken to define the effect of a carbonic anhydrase inhibitor, acetazolamide (AZA), in IR-induced ALI, that was conducted in a rat model of isolated-perfused lung with 30 minutes of ischemia and 90 minutes of reperfusion. The animals were divided into six groups (n = 6 per group): sham, sham + AZA 200 mg/kg body weight (BW), IR, IR + AZA 100 mg/kg BW, IR + AZA 200 mg/kg BW and IR+ AZA 400 mg/kg BW. IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, pulmonary hypertension, neutrophilic sequestration, and an increase in the expression of pro-inflammatory cytokines. Increases in carbonic anhydrase expression and perfusate pCO2 levels were noted, while decreased Na-K-ATPase expression was noted after IR. Administration of 200mg/kg BW and 400mg/kg BW AZA significantly suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1, IL-6 and IL-17) and attenuated IR-induced lung injury, represented by decreases in pulmonary hyper-permeability, pulmonary edema, pulmonary hypertension and neutrophilic sequestration. AZA attenuated IR-induced lung injury, associated with decreases in carbonic anhydrase expression and pCO2 levels, as well as restoration of Na-K-ATPase expression.

| S-EPMC5482472 | biostudies-literature

Evolutionary conserved mutations in PhoPR attenuate the virulence of animal-adapted tuberculosis strains for humans

Project description:By genome comparison of 30 MTBC strains, we identified three SNPs affecting the phoPR genes of members of the animal and M. africanum lineages that were not seen in the M. tuberculosis sensu-stricto genomes. The genes phoPR encode a two component regulatory system that is known for its strong impact on virulence and immunogenicity of M. tuberculosis due to its key role in the regulation of genes involved in lipid synthesis and secretion of the 6 kDa secreted antigenic target ESAT-6. To explore whether these SNPs affect the expression of the PhoP regulon, we compared the transcriptome of M. tuberculosis mutants lacking the endogenous phoPR genes (M-NM-^TphoPR) and their complemented derivatives expressing either the M. bovis or M. tuberculosis allele of phoPR (phoPR-bovis and phoPR-TB respectively). These comparisons were performed in parallel in two M. tuberculosis strains from distinct genetic backgrounds, i.e. strain GC1237 from lineage 2 (also named East-Asia or Beijing cluster) and the H37Rv reference strain from lineage 4 (also named Euro-American cluster). To perform the transcriptomic comparison of the different M. tuberculosis variants (M-NM-^TphoPR, complemented and wt) from the two distinct genetic background, a customized micro-array has been designed then manufactured by Agilent (8 x 15k format). The design of oligonucleotides covering all protein coding sequences was done using OligoArray version 2.1 on the basis of the 3924 predicted coding sequences composing the entire M. tuberculosis H37Rv reference genome. The experimental data for each of the comparison consisted of 4 hybridizations (2 biological replicates with dye-swap); 16 in the end for each genetic background.

2014-07-07 | E-GEOD-54421 | biostudies-arrayexpress

carbonic anhydrase (1 or 2) simple or double mutants-Comparative transcriptome analysis between carbonic anhydrase mutants and wild type Arabidopsis

Project description:cea05-01_carbonic-anhydrase - carbonic anhydrase (1 or 2) simple or double mutants - Identification of genes differentially expressed in leaves of single CA1 and CA2 T-DNA insertional mutants and in the corresponding double mutant vs wild type - CA1 (At3g01500) and CA2 (At5g14740) T-DNA insertional mutant lines, the double (CA1+CA2) mutant and wild type Arabidopsis seeds were sown in soil in a phytotron. Leaves were harvested 40 days later for RNA extraction

2012-03-25 | GSE36625 | GEO

carbonic anhydrase (1 or 2) simple or double mutants-Comparative transcriptome analysis between carbonic anhydrase mutants and wild type Arabidopsis

2012-03-25 | E-GEOD-36625 | biostudies-arrayexpress

SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration.

Project description:BackgroundIn response to hypoxia, tumor cells undergo transcriptional reprogramming including upregulation of carbonic anhydrase (CA) IX, a metalloenzyme that maintains acid-base balance. CAIX overexpression has been shown to correlate with poor prognosis in various cancers, but the role of this CA isoform in hepatoblastoma (HB) has not been examined.MethodsWe surveyed the expression of CAIX in HB specimens and assessed the impact of SLC-0111, a CAIX inhibitor, on cultured HB cells in normoxic and hypoxic conditions.ResultsCAIX immunoreactivity was detected in 15 out of 21 archival pathology HB specimens. The CAIX-positive cells clustered in the middle of viable tumor tissue or next to necrotic areas. Tissue expression of CAIX mRNA was associated with metastasis and poor clinical outcome of HB. Hypoxia induced a striking upregulation of CAIX mRNA and protein in three HB cell models: the immortalized human HB cell line HUH6 and patient xenograft-derived lines HB-295 and HB-303. Administration of SLC-0111 abrogated the hypoxia-induced upregulation of CAIX and decreased HB cell viability, both in monolayer and spheroid cultures. In addition, SLC-0111 reduced HB cell motility in a wound healing assay. Transcriptomic changes triggered by SLC-0111 administration differed under normoxic vs. hypoxic conditions, although SLC-0111 elicited upregulation of several tumor suppressor genes under both conditions.ConclusionHypoxia induces CAIX expression in HB cells, and the CAIX inhibitor SLC-0111 has in vitro activity against these malignant cells.

| S-EPMC9909558 | biostudies-literature

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