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The cyclic-AMP binding domain of the efflux pump Rv3728 acts as a regulator of phosphatidyl-myo-inositol mannosides composition in Mycobacterium tuberculosis

ABSTRACT: Tuberculosis (TB) is an ancient disease caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). The rise of antimicrobial resistance (AMR) threatens to bring Mtb to the forefront of bacterial pathogens as the current treatments are increasingly becoming ineffective. Understanding the development of AMR and the virulence processes of Mtb is crucial for the identification of new drug targets and the rational design of anti-TB treatments. One of the established mechanisms of resistance is through the function of efflux proteins, which are transmembrane transporters that bind and remove antibiotic molecules out from the cell. Here, we determine the role of Rv3728, a major facilitator superfamily (MFS) efflux pump protein, which also predicted to bind 3',5'-cyclic adenosine monophosphate (cAMP). Using bioinformatic tools and cAMP binding assay, we confirm that Rv3728 binds to cAMP and identified E597 and R606 as important residues involved in binding. Although Rv3728 deletion has no impact on bacterial resistance and tolerance to different antibiotics, it affects membrane permeability and alters the acylation profile of phosphatidyl-myo-inositol mannosides lipids.

ORGANISM(S): Mycobacterium tuberculosis H37Rv

PROVIDER: GSE268977 | GEO | 2024/06/10

REPOSITORIES: GEO

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Project description:The innate immune system provides the first response to pathogen infection and orchestrates the activation of the adaptive immune system. Though a large component of the innate immune response is common to all infections, pathogen-specific innate immune responses have been documented as well. The innate immune response is thought to be especially critical for fighting infection with Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB). While TB can be a deadly disease, only 5-10% of individuals infected with MTB develop active disease, and this inter-individual variation is, at least partly, heritable. Studies of inter-individual variation in the innate immune response to MTB infection may therefore shed light on the genetic basis for variation in susceptibility to TB. Yet, to date, we still do not know which properties of the innate immune response are specific to MTB infection and which represent a general response to pathogen infection. To begin addressing this gap, we infected macrophages with eight different bacterial pathogens, including different MTB strains and related mycobacteria, and studied the transcriptional response to infection. We found that although the gene expression changes were largely consistent across the bacterial infection treatments, we were able to identify a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. Genetic variants that are associated with regulatory differences in these genes should be considered candidate loci for explaining inter-individual susceptibility TB. RNA-seq of monocyte-derived macrophages isolated from 6 healthy European males at 4, 18, and 48 hours post-infection with the following 8 bacteria: Mycobacterium tuberculosis (MTB) H37Rv, Mycobacterium tuberculosis GC1237, MTB GC1237, bacillus Calmette-Guérin (BCG), Mycobacterium smegmatis, Yersinia pseudotuberculosis, Salmonella typhimurium, and Staphylococcus epidermidis. table-s1.txt is a tab-delimited text file that contains the batch-corrected log2 counts per million for each of the 156 samples, as well as the Ensembl gene ID and gene name. BCG = bacillus Calmette-Guérin GC = Mycobacterium tuberculosis GC1237 Rv = Mycobacterium tuberculosis (MTB) H37Rv Rv+ = heat-inactivated MTB H37Rv Salm = Salmonella typhimurium Smeg = Mycobacterium smegmatis Staph = Staphylococcus epidermidis Yers = Yersinia pseudotuberculosis

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The cyclic-AMP binding domain of the efflux pump Rv3728 acts as a regulator of phosphatidyl-myo-inositol mannosides composition in Mycobacterium tuberculosis

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