Mycobacteroides abscessus
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ABSTRACT:
PROVIDER: PRJNA669041 | ENA |
REPOSITORIES: ENA
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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: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:In-host adaptation of clinical mycobacterium abscessus isolates
| PRJNA882917 | ENA
Project description:Genome analysis of the Mycobacterium abscessus clinical isolates
| PRJDB16220 | ENA
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:Bacille Calmette Guerin (BCG) is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) disease. However, BCG has limited efficacy, necessitating the development of better vaccines. Non-tuberculous mycobacteria (NTM), a distinct lineage from Mtb, are opportunistic pathogens present in the environment. TB endemic countries experience higher exposure to NTM, but previous studies have not elucidated the relationship between NTM exposure and BCG efficacy. Therefore, we developed a mouse model (BCG+NTM) that mimics human BCG vaccination at an early stage and continuous NTM exposure via the oral route, including during TB infection. Our results show that BCG+NTM mice had improved protection against pulmonary TB correlating with increased pulmonary influx of B-cells, higher titers of anti-Mtb IgA and IgG antibodies in serum and airways, compared to mice vaccinated with BCG alone. Notably, the lungs of BCG+NTM mice developed B-cell aggregates expressing markers of germinal center formation as determined by spatial transcriptomics. We conclude a direct correlation between NTM exposure and protection from TB, with B-cells playing a crucial role.
2022-10-23 | GSE203037 | 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:Mycobacterium abscessus is one of the common clinical non-tuberculous mycobacteria (NTM) which can cause severe skin infections. 5-Aminolevulinic acid photodynamic therapy (ALA_PDT) is an emerming effective antimicrobial medication. To explore whether ALA_PDT can treat M. abscessus infections, we found that ALA_PDT can kill M. abscesses via colony forming unit method. ALA_PDT promoted ferroptosis-like death of M. abscesses, and the antioxidant N-Acetyl-L-cysteine (NAC) and ferroptosis inhibitor Ferrostatin-1(Fer-1) can mitigate the ALA_PDT-mediated sterilization. Furthermore, ALA_PDT significantly up-regulated the transcription of heme oxygenase MAB_4773, increased the intracellular Fe2+ concentration, altering the transcription of M. abscessus iron metabolism genes. ALA_PDT disrupted the integrity of the cell membrane and enhanced the permeability of the cell membrane, as evidenced by the boosted sterilization effect of antibiotics. In summary, ALA_PDT can kill M. abscesses via promoting the ferroptosis-like death and antibiotic sterilization through oxidative stress. This new mechanism of ALA_PDT against M. abscessus might underlie its clinical efficacy.
2022-03-30 | GSE193092 | GEO
Project description:Whole genome sequencing of top priority nontuberculous mycobacteria used in preclinical compound testing at Colorado State University
| PRJNA191787 | ENA
Project description:Aging has a significant impact on the immune system, leading to a gradual decline in immune function and changes in the body's ability to respond to bacterial infections. Non-tuberculous mycobacteria (NTM), also known as atypical mycobacteria or environmental mycobacteria, are commonly found in soil, water, and various environmental sources. While many NTM species are considered opportunistic pathogens, some can cause significant infections, particularly in individuals with compromised immune systems, such as the elderly. When mycobacteria enter the body, macrophages are among the first immune cells to encounter them, and attempt to engulf mycobacteria through a process called phagocytosis. Some NTM species, including Mycobacterium avium (M.avium) can survive and replicate within macrophages. However, little is known about the interaction between NTM and macrophages in the elderly. In this study, we investigated the mouse bone marrow-derived macrophage (BMMs) response to M. avium serotype 4, one of the main NTM species in patients with pulmonary NTM diseases. Our results demonstrated that old mouse BMMs have an increased level of intracellular iron and are more susceptible to M. avium serotype 4 infection compared to young mouse BMMs. The whole-cell proteomic analysis indicated a dysregulated expression of iron homeostasis-associated proteins in old mouse BMMs regardless of mycobacterial infection. Deferoxamine, an iron chelator, significantly rescued mycobacterial killing and phagolysosome maturation in old mouse BMMs. Therefore, our data indicate that an intracellular iron overload improves NTM survival within macrophages, and suggest a potential application of iron chelating drugs as a host-directed therapy for pulmonary NTM infection in the elderly
2024-05-24 | PXD045821 | Pride