Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1141985 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Hijacking intrinsic resistance in Mycobacterium abscessus with small molecule prodrugs
| PRJNA1142444 | ENA
Project description:We performed total quantitative proteomics on planktonic Mycobacterium abscessus ATCC19977 cells treated with 100 microM of florfenicol amine (FF-NH2 or FFA) treated or vehicle (DMSO) control for 30 minutes and 3 hours to detect unbiased FF-NH2-induced differences in the M. abscessus proteome.
2025-01-15 | MSV000096854 | MassIVE
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
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.
2013-07-17 | GSE43629 | GEO
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
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
Project description:This proposal aims to develop narrow-spectrum prodrug-activated protein synthesis inhibitors to treat Mycobacterium abscessus (Mabs) infections. It builds on a recent discovery in our program, which elucidated a unique mechanism for prodrug activation of florfenicol amine (FFA) by hijacking the protective methods Mabs uses to block antibiotic action. Non-tuberculous mycobacteria (NTM) are emerging pathogens with high intrinsic drug resistance. Mabs is the most pathogenic refractory NTM member,1-3 and infections with this pathogen are associated with especially poor clinical outcomes, similar to XDR-TB (extensively drug-resistant tuberculosis)1. Florfenicol (FF) is a broad-spectrum analog of chloramphenicol (CAM), is orally bioavailable, safely used in agriculture as it lacks some of the pharmacological liabilities of CAM, and it mitigates plasmid-borne resistance by blocking the primary-hydroxy site of inactivation. FFA is the primary metabolite found in many host species after FF administration. Through routine MIC screening of synthetic intermediates, we discovered that FFA on its own had appreciable WhiB7 transcription factor-dependent MIC activity against Mabs. Further studies demonstrated that in Mabs FFA acts as a prodrug that is acylated into the active form (FFac) within Mabs by Eis2, a Mabs specific acetyltransferase. eis2 is located in the whiB7 resistome, which results in a feed-forward mechanism of action between FFA, eis2, and whiB7, ultimately increasing the conversion of FFA to FFac, resulting in increased sensitivity. FFA was found to be highly synergistic with other protein synthesis inhibitors and resistance to FFA by inactivation of whiB7 or eis2 results in increased sensitivity to aminoglycosides and macrolides. Since eis2 is only present in Mabs and other closely related species, FFA has a narrow spectrum of activity and avoids the potential for mitochondrial cytotoxicity. Preliminary pharmacological studies demonstrate FFA is noncytotoxic and orally bioavailable.
2025-07-01 | GSE273574 | GEO
Project description:Non-tuberculous Mycobacteria (NTM) are a group of emerging bacterial pathogens that have been identified in cystic fibrosis (CF) patients with microbial lung infections. The treatment of NTM infection in CF patients is challenging due to the natural resistance of NTM species to many antibiotics. Mycobacterium abscessus (M. abscessus) is one of the most common NTM strains found in the airway of CF patients. In our current study, we characterized the extracellular vesicles (EVs) released by drug-sensitive M. abscessus untreated or treated with clarithromycin, one of the well-known anti-NTM drugs. Our data show that clarithromycin treatment increases mycobacterial protein trafficking into EVs as well as the secretion of EVs in M. abscessus culture. Additionally, EVs released by clarithromycin-treated M. abscessus increase M. abscessus resistance to clarithromycin when compared to EVs from untreated M. abscessus. EV proteomic analysis further indicates that EVs released by clarithromycin-treated M. abscessus carry an increased level of 50S ribosomal subunits, the target of clarithromycin. Taken together, our results suggest that mycobacterial EVs play an important role in increasing M. abscessus resistance to clarithromycin treatment.
2025-05-06 | PXD047862 | Pride
Project description:Mycobacterium abscessus is an opportunistic pathogen notorious for its resistance to most classes of antibiotics and low cure rates. In addition to the highly impermeable mycomembrane, M. abscessus carries an array of shared and species-specific defence mechanisms. However, it remains unknown whether M. abscessus’ antibiotic stress response is fine-tuned or an all-or-nothing response. A deeper understanding of underlying resistance and tolerance mechanisms is pivotal in development of targeted therapeutic regimens. We elucidate the transcriptomic response of M. abscessus to antibiotics recommended in treatment guidelines. The M. abscessus ATCC 19977 strain was used. Bacteria were subjected to sub-inhibitory concentrations of drugs for 4- and 24-hours, followed by RNA sequencing. In addition, time-kill kinetic analysis was performed using bacteria after pre-exposure to clarithromycin, amikacin or tigecycline for 24-hours. Lastly, Pan-genome analysis of 35 strains from all three subspecies was performed. Mycobacterium abscessus shows both drug-specific and communal transcriptomic responses to antibiotic exposure. Key features of its tolerance to antibiotics are drug-specific converting enzymes, target protection and shifts in its respiratory chain and metabolic state. The observed transcriptomic responses are likely not strain-specific, as genes involved in tolerance are found in all included strains, with the exception of erm(41) in M. abscessus subspecies massiliense. Due to the communal response elicited by ribosomal-targeting antibiotics, exposure to any of these drugs rapidly induces tolerance mechanisms that decrease susceptibility to ribosome-targeting drugs from multiple classes. Screening high-risk patients (e.g. those with bronchiectasis) for M. abscessus infection prior to starting macrolide or aminoglycoside maintenance therapy is warranted.
2022-01-25 | GSE163621 | GEO
Project description:Mycobacterium abscessus HelR interacts with RNA Polymerase to confer intrinsic rifamycin resistance
| PRJNA830343 | ENA