Identification of the anti-mycobacterial functional properties of piperidinol derivatives
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB15140 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR1588780_1.fastq.gz | Fastqsanger.gz | |||
| ERR1588780_2.fastq.gz | Fastqsanger.gz | |||
| ERR1588781_1.fastq.gz | Fastqsanger.gz | |||
| ERR1588781_2.fastq.gz | Fastqsanger.gz | |||
| ERR1588782_1.fastq.gz | Fastqsanger.gz |
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Project description:Background and purposeTuberculosis (TB) remains a major global health threat and is now the leading cause of death from a single infectious agent worldwide. The current TB drug regimen is inadequate, and new anti-tubercular agents are urgently required to be able to successfully combat the increasing prevalence of drug-resistant TB. The purpose of this study was to investigate a piperidinol compound derivative that is highly active against the Mycobacterium tuberculosis bacillus.Experimental approachThe antibacterial properties of the piperidinol compound and its corresponding bis-Mannich base analogue were evaluated against M. smegmatis and Gram-negative organisms. Cytotoxicity studies were undertaken in order to determine the selectivity index for these compounds. Spontaneous resistant mutants of M. smegmatis were generated against the piperidinol and corresponding bis-Mannich base lead derivatives and whole genome sequencing employed to determine the genetic modifications that lead to selection pressure in the presence of these compounds.Key resultsThe piperidinol and the bis-Mannich base analogue were found to be selective for mycobacteria and rapidly kill this organism with a cytotoxicity selectivity index for mycobacteria of >30-fold. Whole genome sequencing of M. smegmatis strains resistant to the lead compounds led to the identification of a number of single nucleotide polymorphisms indicating multiple targets.Conclusion and implicationsOur results indicate that the piperidinol moiety represents an attractive compound class in the pursuit of novel anti-tubercular agents.Linked articlesThis article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc.
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Project description:The emergence of multi-drug resistant pathogens is a major public health problem, leading to rethink and innovate in our bacterial control strategies. Here, we explore the anti-biofilm and anti-virulence activities of nineteen 6-polyaminosterol derivatives (squalamine-based), presenting a modulation of their polyamine side chain, on 4 major pathogens, i.e. carbapenem-resistant A. baumannii (CRAB) and P. aeruginosa (CRPA), a methicillin-resistant S. aureus (MRSA) and a vancomycin-resistant E. faecium (VRE) strains. We screened the effect of these derivatives on biofilm formation and eradication. 4e (for CRAB, VRE and MRSA) and 4f (for all the strains) were the most potent one and displayed activities as good as conventional antibiotics. We also identified 11 compounds able to decrease by more than 40% the production of pyocyanin, a major virulence factor of P. aeruginosa. We demonstrated that 4f treatment acts against bacterial infections in Galleria mellonella and significantly prolonged the larvae survival (from 50% to 80%) after 24 h of CRAB, VRE and MRSA infections. As shown by proteomic studies, 4f triggered distinct cellular responses depending on the bacterial species, but essentially related to the cell envelop. Its interesting anti-biofilm and anti-virulence properties make it promising candidate for use in therapeutics.
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Project description:The anti-mycobacterial activity of C17 diynes has been described previously, however, their mode of action remains unknown. Microarray techniques were used to explore the genetic regulation reponses of Mycobacterium smegmatis to treatment with the C17 diynes, falcarinol and panaxydol. Our analyses showed a distinct mode of action of the C17 diynes when compared with commonly used anti-mycobacterial drugs. In addition, geneset enrichment analysis, pathway enrichment analysis and PASS analysis revealed significant gene ontology terms, pathways and potential modes of action, respectively. Combing the results of the three analyses, we hypothesize that the C17 diynes inhibit fatty acid biosynthesis, specifically phospholipid synthesis in mycobacteira. Mycobacterium smegmatis MC2 155 was treated with 10 times of MIC90 of falcarinol, panaxydol, isoniazid, ethambutol and kanamycin for 6 hours with at least 6 independent biological replicates.
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Project description:The anti-mycobacterial activity of C17 diynes has been described previously, however, their mode of action remains unknown. Microarray techniques were used to explore the genetic regulation reponses of Mycobacterium smegmatis to treatment with the C17 diynes, falcarinol and panaxydol. Our analyses showed a distinct mode of action of the C17 diynes when compared with commonly used anti-mycobacterial drugs. In addition, geneset enrichment analysis, pathway enrichment analysis and PASS analysis revealed significant gene ontology terms, pathways and potential modes of action, respectively. Combing the results of the three analyses, we hypothesize that the C17 diynes inhibit fatty acid biosynthesis, specifically phospholipid synthesis in mycobacteira.
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2023-12-20 | PXD048020 |
Project description:Mycobacterial arabinogalactan (AG) is an essential cell wall component of Mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Yet, it is unclear whether mycobacterial AG is a pathogen-associated molecular pattern (PAMP) with an elusive pattern recognition receptor (PRR). Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibited cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increased survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacted with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associated with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocked AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravated the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.
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