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

ABSTRACT: 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.

ORGANISM(S): Mycobacteroides abscessus subsp. bolletii Mycobacteroides abscessus

PROVIDER: GSE43629 | GEO | 2013/07/17

SECONDARY ACCESSION(S): PRJNA186855

REPOSITORIES: GEO

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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

Overlap in antibiotic stress responses leads to cross-resistance between ribosomal acting drugs in Mycobacterium abscessus.

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

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

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

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

| PRJNA186855 | ENA

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

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

Project description:Klebsiella species typing scheme development

| PRJEB10286 | ENA

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

Dual RNA-sequencing of macrophages infected with Mycobacterium avium reveals host-pathogen interaction in the context of clarithromycin treatment

Project description:Background: Mycobacterium avium is an opportunistic pathogen that requires complex multidrug treatment. Macrolides, like clarithromycin, are the cornerstone of treatment, but even macrolide-based treatment regimens have suboptimal outcomes. Combining transcriptomic profiling of macrophages and mycobacteria in an in vitro infection model may increase our understanding of the host-pathogen interaction and the effect of antibiotic treatment. Methods: To investigate the molecular interplay between pathogen and host, we developed an optimized protocol for dual RNA-sequencing of human monocyte-derived macrophages infected with M. avium. Results: Upon phagocytosis, host defense processes including immune activation and pathogen recognition were upregulated, while M. avium upregulated expression of PE/PPE genes, which are important for immune recognition. Clarithromycin did not affect gene regulation of the host; the effect of clarithromycin on M. avium gene expression was very different in RPMI compared to intracellular mycobacteria, likely due to the influence of the host environment on expression of the important regulatory WhiB genes. Conclusions These data identify the distinct stress responses of M. avium upon infection and clarithromycin treatment and underline the importance of taking the intracellular localization and interaction with the host into account when studying antibiotics against intracellular pathogens.

2024-01-01 | GSE213117 | GEO

Dissecting the antibacterial activity of Oxadiazolone-core derivatives against Mycobacterium abscessus

Project description:Mycobacterium abscessus is nowadays under the spotlight of the scientific community. This pathogenic mycobacteria is indeed responsible for a wide spectrum of infections involving mostly pulmonary infections in patients with cystic fibrosis. M. abscessus is intrinsically resistant to a broad range of antibiotics, including most antitubercular drugs, and is considered the most pathogenic and chemotherapy-resistant rapidly growing mycobacterium. Consequently, with very limited treatment options, the development of new therapeutic approaches to fight this pathogen are urgently needed. In this context, 19 oxadiazolone (OX) derivatives have been investigated for their antibacterial activity against both the rough (R) and smooth (S) variants of M. abscessus. Several OXs were active against extracellular M. abscessus growth with moderated minimal inhibitory concentrations (MIC), or intracellularly by inhibiting M. abscessus growth inside infected macrophages with MIC values similar to those of imipenem. Such promising results prompted us to identify the potential target enzymes of the sole extra and intracellular inhibitor of M. abscessus growth, i.e., iBpPPOX via activity-based protein profiling combined with mass spectrometry. This approach led to the identification of 21 potential protein candidates being mostly involved in M. abscessus lipid metabolism and/or in cell wall biosynthesis.

2020-08-14 | PXD015680 | Pride

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