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Mycobacterium abscessus HelR interacts with RNA Polymerase to confer intrinsic rifamycin resistance

ABSTRACT: Using RNA sequencing we show that exposure of M. abscessus to sublethal doses of RIF results in ~25-fold upregulation of Mab_helR; an isogenic deletion mutant of Mab_helR is hypersensitive to RIF and RBT, and over-expression of Mab_helR confers RIF tolerance in M. tuberculosis, implying that Mab_helR constitutes a significant determinant of inducible RIF and RBT resistance.

ORGANISM(S): Mycobacteroides abscessus

PROVIDER: GSE201201 | GEO | 2022/07/27

REPOSITORIES: GEO

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Mycobacterium abscessus HelR interacts with RNA polymerase to confer intrinsic rifamycin resistance.

Project description:Rifampicin (RIF), the frontline drug against M. tuberculosis, is completely ineffective against M. abscessus, partially due to the presence of an ADP-ribosyltransferase (Arr) that inactivates RIF. Using RNA-seq, we show that exposure of M. abscessus to sublethal doses of RIF and Rifabutin (RBT), a close analog of RIF, results in an ∼25-fold upregulation of Mab_helR in laboratory and clinical isolates. An isogenic deletion in Mab_helR results in RIF/RBT hypersensitivity, and overexpression of Mab_helR confers RIF tolerance in M. tuberculosis. We demonstrate an increased HelR-RNAP association in RIF-exposed bacteria and a MabHelR-mediated dissociation of RNAP from stalled initiation complexes in vitro. Finally, we show that the tip of the PCh-loop of Mab_helR, present in proximity to RIF, is critical for conferring RIF resistance but dispensable for dissociation of stalled RNAP complexes, suggesting that HelR-mediated RIF resistance requires a step in addition to displacement of RIF-stalled RNAP.

| S-EPMC9444957 | biostudies-literature

Mycobacterium abscessus HelR interacts with RNA Polymerase to confer intrinsic rifamycin resistance

Project description:Mycobacterium abscessus HelR interacts with RNA Polymerase to confer intrinsic rifamycin resistance

| PRJNA830343 | ENA

Human pluripotent stem cell-derived macrophages host Mycobacterium abscessus infection

Project description:Human macrophages are a natural host of many mycobacterium species, including Mycobacterium abscessus (M. abscessus), an emerging pathogen affecting patients with lung diseases and immunocompromised individuals. There are few available treatments and the search for effective antibiotics against M. abscessus has been hindered by the lack of a tractable in vitro intracellular model of infection. Here, we established a reliable model for M. abscessus infection using human pluripotent stem cell-derived macrophages (hPSC-macrophages). hPSC differentiation permitted a reproducible generation of functional human macrophages that were highly susceptible to M. abscessus infection. Electron microscopy demonstrated that M. abscessus was present in the vacuoles of hPSC-macrophages. RNA-sequencing analysis revealed a time dependent host cell response to M. abscessus, with differing gene and protein expression patterns observed at 3-hours, 24-hours and 48-hours post-infection. Culture of engineered tdTOMATO-expressing hPSC-macrophages with GFP-expressing M. abscessus enabled rapid and image-based high-throughput analysis of intracellular infection and quantitative assessment of antibiotic resistance and efficacy. Our study describes the first hPSC-based model for M. abscessus infection, which represents a novel platform for studying M. abscessus-host interaction and an accessible tool for drug discovery.

2022-08-10 | GSE207456 | GEO

Mycobacterium abscessus virulence traits unraveled by transcriptomic profiling in amoebae and macrophages

Project description:We report the transcriptome of M. abscessus in amoebae and macrophages. M. abscessus intra-amoebal and intra-macrophagic transcriptomes demonstrate of the potential of M. abscessus to adapt to an intracellular lifestyle, though amoebae largely contribute to the enhancement of M. abscessus survival macrophages.

2019-09-20 | GSE124972 | GEO

Neutrophil gene expression in response to Mycobacterium abscessus

Project description:The response of human neutrophils to the emerging pathogen Mycobacterium abscessus has not been described. However, M. abscessus infections are frequently associated with neutrophil-rich abscesses. To better understand the reponse of neutrophils to M. abscessus we performed gene expression analysis using Affymetrix HG-U133A Plus 2.0 microarrays. Human neutrophils from healthy donors were stimulated with isogenic rough and smooth morphotypes of M. abscessus. Staphylococcus aureus was used as a control. Gene expression was compared to neutrophils left unstimulated. Neutrophils from four individual donors were isolated on separate days and stimulated with freshly prepared bacteria. Neutrophils (stimulated and control) were left for 2 hours before total RNA was isolated, and biotinylated cRNA was prepared by standard methods. Analysis indicates that M. abscessus morphotypes induce a limited number of genes, when compared to S. aureus, which are enriched in genes for cytokines and chemokines, including neutrophil-specific chemokines. These data suggest that neutrophils have a limited response to M. abscessus, which may contribute to neutrophil-rich abscess formation.!Series_overall_design = Human neutrophils from healthy donors were exposed to rough Mab (ATCC 19977T), smooth Mab (ATCC 19977T) and S. aureus (CF clinical strain) for two hours; control cells were exposed to saline.

2013-01-10 | GSE39889 | GEO

RNA sequencing of Mycobacterium abscessus under infection-relevant conditions

Project description:RNA sequencing (RNA-seq) of Mycobacterium abscessus in four infection-relevant culture conditions: hypoxic stress, artificial sputum medium, kanamycin-treated medium, and erythromycin-treated medium. Triplicate cultures of M. abscessus were grown in (1) Artificial Sputum media, (2) hypoxic conditions, (3) the presence of kanamycin, and (4) the presence of erythromycin. Triplicate controls were prepared for sample (1) and samples (2-4).

2016-03-02 | E-GEOD-78787 | biostudies-arrayexpress

New rapid scheme for distinguishing subspecies of the Mycobacterium abscessus group and identification of Mycobacterium massiliense with inducible clarithromycin resistance

Project description:Mycobacterium abscessus [M. abscessus (sensu lato) or M. abscessus group] comprises three closely related taxa with taxonomic status under revision: M. abscessus sensu stricto, M. bolletii and M. massiliense. We describe here a simple, robust and cost effective PCR-based method for distinguishing among M. abscessus, M. massiliense and bolletii. Based on the M. abscessus ATCC 19977T genome, discriminatory regions were identified between M. abscessus and M. massiliense from array-based comparative genomic hybridization. A typing scheme using PCR primers designed for four of these locations was applied to 46 well-characterized clinical isolates comprising 29 M. abscessus, 15 M. massiliense and 2 M. bolletii previously identified by multi-target sequencing. Interestingly, 2 isolates unequivocally identified as M. massiliense were shown to have a full length erm(41) instead of the expected gene deletion and showed inducible clarithromycin resistance after 14 days. We propose using this PCR-based typing scheme combined with erm(41) PCR for a straightforward identification of M. abscessus, M. massiliense and M. bolletii and assessment of inducible clarithromycin resistance. This method can be easily implemented into a routine workflow providing subspecies level identification within 24 hours of isolation of M. abscessus group. Two-color CGH with 4 independent Mycobacterium clinical isolates and the M massiliense type strain (CCUG 48898) labeled with Cy3 were cohybridized with the M abscessus type strain (ATCC 19977) labeled with Cy5 on a tiling array designed against the M abscessus type strain

2013-07-17 | E-GEOD-43629 | biostudies-arrayexpress

Mycobacteroides abscessus subsp. abscessus

Project description:Mycobacterium abscessus subsp. abscessus re-sequencing

| PRJNA734909 | ENA

Spectinomycin Analogs for the Treatment of Mycobacterium abscessus Infections

Project description:Non-tuberculous mycobacteria (NTM) are emerging pathogens with high intrinsic drug resistance. Among rapidly growing NTM species, Mycobacterium abscessus is among the most pathogenic. Standard of care therapy has led to unacceptable outcomes and demonstrates the urgent need to develop effective, broad-spectrum antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), an aminocyclitol antibiotic, we have identified a distinct structural subclass of ethylene linked aminomethyl spectinomycins (eAmSPC) that are up to 64-fold more potent against M. abscessus when compared to SPC. Lead eAmSPC retain activity against other NTM species and multi-drug resistant M. abscessus clinical isolates. Sequencing of eAmSPC-resistant mutants revealed nucleotide changes in the distinct helix-34 spectinomycin binding site and X-ray crystallography further demonstrated the derivatives mode of ribosomal inhibition remained on target. The eAmSPC displayed increased intracellular accumulation compared to SPC and transcriptional profiling indicate that eAmSPC’s induce whiB7 resistance responses, however, the series maintains potency despite its expression. These leads display favorable pharmacokinetic profiles and robust efficacy in M. abscessus mouse infection models. The results of these studies suggest that eAmSPCs have the potential to be developed into clinical treatments for M. abscessus and other NTM infections.

2023-01-09 | GSE222081 | GEO

Computational drug repositioning identifies niclosamide and tribromsalan as inhibitors of Mycobacterium tuberculosis and Mycobacterium abscessus

Project description:Tuberculosis (TB) is still a major global health challenge, killing over 1.5 million people each year, and hence, there is a need to identify and develop novel treatments for Mycobacterium tuberculosis (M. tuberculosis). The prevalence of infections caused by nontuberculous mycobacteria (NTM) is also increasing and has overtaken TB cases in the United States and much of the developed world. Mycobacterium abscessus (M. abscessus) is one of the most frequently encountered NTM and is difficult to treat. We describe the use of drug-disease association using a semantic knowledge graph approach combined with machine learning models that has enabled the identification of several molecules for testing anti-mycobacterial activity. We established that niclosamide (M. tuberculosis IC90 2.95 μM; M. abscessus IC90 59.1 μM) and tribromsalan (M. tuberculosis IC90 76.92 μM; M. abscessus IC90 147.4 μM) inhibit M. tuberculosis and M. abscessus in vitro. To investigate the mode of action, we determined the transcriptional response of M. tuberculosis and M. abscessus to both compounds in axenic log phase, demonstrating a broad effect on gene expression that differed from known M. tuberculosis inhibitors. Both compounds elicited transcriptional responses indicative of respiratory pathway stress and the dysregulation of fatty acid metabolism. Further testing against drug-resistant isolates and other NTM is warranted to clarify the usefulness of these repurposed drugs for mycobacteria.

2024-03-01 | E-MTAB-13761 | biostudies-arrayexpress

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