Defining the mechanisms-of-action of nitrofuranyl piperazines against Mycobacterium abscessus
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ABSTRACT:
PROVIDER: PRJNA1214848 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32098700_1.fastq.gz | Fastqsanger.gz | |||
| SRR32098700_2.fastq.gz | Fastqsanger.gz | |||
| SRR32098691_1.fastq.gz | Fastqsanger.gz | |||
| SRR32098691_2.fastq.gz | Fastqsanger.gz | |||
| SRR32098692_1.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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