Ontology highlight
ABSTRACT:
PROVIDER: PRJNA815471 | ENA |
REPOSITORIES: ENA
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Project description:There is an urgent need for novel antibiotics against carbapenem and 3rd generation cephalosporin-resistant Gram-negative pathogens, for which the last-resort antibiotics have lost most of their efficacy. We describe here a novel class of synthetic antibiotics that was inspired from natural product-derived scaffolds. The antibiotics have an unprecedented mechanism of action, which targets the main component (BamA) of the Bam folding machinery required for folding and insertion of ß-barrel proteins into the outer membrane of Gram-negative bacteria. This OMPTA (outer membrane protein-targeting antibiotic) class shows potent activity against multidrug-resistant Gram-negative ESKAPE pathogens and overcomes colistin-resistance both in vitro and in vivo. A clinical candidate has the potential to address life threatening Gram-negative infections with high unmet medical need.
2020-02-04 | MSV000084899 | MassIVE
Project description:The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum -lactamase (ESBL)-producing bacteria is a critical threat to human health, and new treatment strategies are urgently required. Here, we investigated the ability of the safe-for-human use ionophore PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 was observed to resensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including the less-toxic next-generation polymyxin derivative, FADDI-287. We were unable to select for mutants resistant to PBT2 + FADDI-287 in polymyxin resistant E. coli containing a plasmid-borne mcr-1 gene or K. pneumoniae carrying a chromosomal mgrB mutation. Using a highly invasive K. pneumoniae strain engineered for polymyxin resistance through mgrB mutation, we successfully demonstrated the efficacy of PBT2 + FADDI-287 in vivo for the treatment of Gram-negative sepsis. These data present a new treatment modality to break antibiotic resistance in high priority polymyxin-resistant Gram-negative pathogens.
2020-07-01 | GSE153553 | GEO
Project description:There is an urgent need for novel antibiotics against carbapenem and 3rd generation cephalosporin-resistant Gram-negative pathogens, for which the last-resort antibiotics have lost most of their efficacy. We describe here a novel class of synthetic antibiotics that was inspired from natural product-derived scaffolds. The antibiotics have an unprecedented mechanism of action, which targets the main component (BamA) of the Bam folding machinery required for folding and insertion of ß-barrel proteins into the outer membrane of Gram-negative bacteria. This OMPTA (outer membrane protein-targeting antibiotic) class shows potent activity against multidrug-resistant Gram-negative ESKAPE pathogens and overcomes colistin-resistance both in vitro and in vivo. A clinical candidate has the potential to address life threatening Gram-negative infections with high unmet medical need.
2019-10-22 | PXD010174 | Pride
Project description:The race to combat antibiotic resistance and develop novel therapies has triggered studies on novel metal-based formulations. Silver remains a strong candidate since ancient times due to its multimodal and broad-spectrum activity against bacterial and fungal pathogens. N-heterocyclic carbene (NHC) complexes coordinate transition metals to generate a broad range of anticancer and/or antimicrobial agents with ongoing efforts being made to enhance lipophilicity and drug stability. The lead silver(I) acetate complex, 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) (SBC3) synthesised by the Tacke group has previously demonstrated promising growth and biofilm-inhibiting properties. As an extension of this, we examined the responses of two structurally different bacteria to SBC3 using label-free quantitative proteomic analysis. Multidrug resistant Pseudomonas aeruginosa (Gram-negative) and Staphylococcus aureus (Gram-positive) are associated with chronic wound infections and Cystic Fibrosis lung colonisation where co-infection often exacerbates disease. SBC3 increased the abundance of alginate biosynthesis, secretion system and drug detoxification proteins in P. aeruginosa whilst a multitude of pathways including anaerobic respiration, twitching motility, and ABC transport were decreased. This contrasted with affected pathways in S. aureus such as increased DNA replication/repair and cell redox homeostasis and decreased protein synthesis, lipoylation, glucose metabolism. Increased abundance of cell wall/membrane proteins were indicative of the structural damage induced by SBC3 to both cell types. These findings show the potential broad applications of SBC3 in treating Gram-positive and Gram-negative bacteria.
2023-03-11 | PXD038616 | Pride
Project description:Drug resistance and tolerance eliminate the therapeutic potential of antibiotics against pathogens. Antibiotic tolerance by bacterial biofilms often leads to persistent infections, but its mechanisms are unclear. To uncover antibiotic tolerance mechanisms in biofilms, we applied stable isotope labeling with amino acids (SILAC) proteomics to selectively label and compare proteomes of sensitive and tolerant subpopulations of biofilms formed by Pseudomonas aeruginosa towards colistin, a 'last-resort' antibiotic against multidrug-resistant Gram-negative pathogens. Migration was essential in forming colistin-tolerant biofilm subpopulations, as colistin-tolerant cell-aggregates migrated with type IV pili, onto the top of killed biofilm. The colistin-tolerant cell-aggregates employed quorum sensing (QS) to initiate the formation of fresh colistin-tolerant subpopulations, highlighting multicellular behavior in antibiotic tolerance development. Erythromycin treatment which inhibits motility and QS, boosted biofilm eradication by colistin. This novel ‘-omics’ strategy to study antibiotic tolerant cells provides key insights for designing novel treatments against infections unsuppressed by conventional antimicrobials.
2016-02-16 | PXD002369 | Pride
Project description:Allicin, a volatile diallylthiosulfinate from garlic (Allium sativum), exhibits broad-spectrum activity against microbial pathogens. It disrupts thiol and redox homeostasis, proteostasis, and cell membrane integrity leading to inactivation of even multidrug resistant strains. Since medicine demands cost-efficient antimicrobials with so far unexploited mechanisms, allicin with its multifaceted mode of action is a promising lead structure for future therapeutics. However, while progress is being made in fully unraveling its mode of action, little is known on bacterial adaptation strategies to cope with allicin-like stress. Some isolates of Pseudomonas aeruginosa and Escherichia coli, withstand exposure to higher allicin concentrations than other bacteria due to as yet unknown cellular mechanisms. To elucidate resistance and sensitivity-conferring cellular processes we compared the acute proteomic responses of the resistant species P. aeruginosa and sensitive species Bacillus subtilis to the published proteomic response of E. coli to allicin treatment. The cellular defense strategies shared functional features: proteins involved in protein (re)folding and repair, ROS and RSS detoxification, and cell envelope modification were upregulated. In both Gram-negative species, protein synthesis of up to 64% of the proteins synthesized in untreated cells was down-regulated while the sensitive, Gram-positive B. subtilis responded by upregulation of multiple regulons. A comparison of the B. subtilis proteomic response to a library of proteomic responses to antibiotic treatment, revealed 30 proteins specifically upregulated by allicin. Other upregulated proteins indicating oxidative stress were shared with nitrofurantoin and diamide. Microscopy-based assays further indicate that in B. subtilis cell wall integrity was impaired.
2021-03-09 | PXD012622 | Pride
Project description:The emergence of colistin resistance in carbapenem-resistant and extended-spectrum ß-lactamase (ESBL)-producing bacteria is a significant threat to human health, and new treatment strategies are urgently required. Here we investigated the ability of the safe-for-human use ionophore PBT2 to restore antibiotic sensitivity in several polymyxin-resistant, ESBL-producing, carbapenem resistant Gram-negative human pathogens. PBT2 was observed to resensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including a ‘next generation’ polymyxin derivative, FADDI-287. To gain additional insight into the potential mechanism of action of PBT2, we analyzed the transcriptome of K. pneumoniae and E. coli in the presence of sub-inhibitory concentrations of PBT2. Treatment with PBT2 was associated with multiple stress responses in both K. pneumoniae and E. coli. Significant changes in the transcription of transition metal ion homeostasis genes were observed in both strains.
2019-06-13 | GSE132637 | GEO