Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus
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PROVIDER: PRJNA729413 | ENA |
REPOSITORIES: ENA
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Project description:Regulation of M. abscessus gene expression in WT or dosR mutant and treated with artemisinin
2024-05-12 | GSE174310 | GEO
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:A search for alternative Mycobacterium abscessus treatments led to our interest in the two-component regulator DosRS, which, in Mycobacterium tuberculosis, is required for the bacterium to establish a state of nonreplicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of dosRS impairs the adaptation of M. abscessus to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We determined that three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, can target DosS-mediated hypoxic signaling in M. abscessus and recapitulate the phenotypic effects of genetically disrupting dosS. OZ439 displayed bactericidal activity comparable to standard-of-care antibiotics in chronically infected mice, in addition to potentiating the activity of antibiotics used in combination. The identification of antimalarial drugs as potent inhibitors and adjunct inhibitors of M. abscessus in vivo offers repurposing opportunities that could have an immediate impact in the clinic.
| S-EPMC8943825 | biostudies-literature
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: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
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: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: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. 38 new analogs of Cyclipostins & Cyclophostin (CyC), compounds naturally produced by Streptomyces species, have been synthesized. Their antibacterial activities against clinical isolates belonging to the M. chelonae-abscessus clade, as well as Gram-negative and Gram-positive bacteria have been evaluated by the REMA method. The intracellular activities of the CyC against intramacrophagic M. abscessus have also been investigated and compared to those of imipenem. The CyCs displayed very low toxicity towards host cells and their inhibitory activity was exclusively restricted to mycobacteria. The best candidate, CyC17, showed a high selectivity for mycobacteria with MIC values (<2 up to 40 µg/mL) comparable to those of most classical antibiotics used to treat M. abscessus infections. Of importance, several CyCs were active against extracellular M. abscessus growth (i.e., CyC17 / CyC18β / CyC25 / CyC26) or against intracellular mycobacteria inside macrophages (i.e., CyC7α,β / CyC8α,β) with MIC values similar to or better than those of standard antibiotics. Based on these results, we intended to identify the potential target enzymes of CyC17/CyC26 in M. abscessus by activity-based protein profiling (ABPP) approach coupled with mass spectrometry differential analysis.
2019-10-08 | PXD014255 | Pride
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