Project description:Plant defensins are a broadly distributed family of antimicrobial peptides which have been primarily studied for agriculturally relevant antifungal activity. Recent studies have probed defensins against gram negative bacteria revealing evidence for multiple mechanisms of action including membrane lysis and ribosomal inhibition. In this study, a γ-core motif synthetic analog ( Atr-DEF2(G39-C55) ) of Amaranthus tricolor DEF2 (Atr-DEF2) is used to probe plant defensin antibacterial mechanism of action via proteomics.
2021-04-14 | PXD024138 | Pride
Project description:In vitro antimicrobial activity of octenidine and chlorhexidine against clinical multidrug-resistant Pseudomonas aeruginosa isolates
Project description:Methylrhodomelol (1) is a bromophenol from the red alga Vertebrata lanosa (L.) T.A.Christensen that has been associated with antimicrobial properties. Aim of the current study was therefore, to assess the antimicrobial potential of this compound in more detail against the gram-negative pathogen Pseudomonas aeruginosa. 1 exerted weak bacteriostatic activity against different strains when grown in minimal medium, whereas other phenolics were inactive. In addition, 1 (35 and 10 µg/mL) markedly enhanced the susceptibility of multidrug resistant P. aeruginosa towards the aminoglycoside gentamicin, while it did not affect the viability of Vero kidney cells up to 100 µM. Finally, pyoverdine release was reduced in bacteria treated at sub-inhibitory concentration, but no effect on other virulence factors was observed. Transcriptome analysis of treated versus untreated P. aeruginosa indicated an interference of 1 with bacterial carbon and energy metabolism, which was corroborated by RT-qPCR and decreased ATP-levels in treated bacteria.
Project description:The synthetic flexicate compound Λ-5b shows potent antimicrobial activity against E. coli. In this study we investigated the transcriptomic response of a clinically relevant E. coli, EHEC O157:H7, to a sublethal concentration of the compound.
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:Phages against multidrug-resistant bacteria
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.
Project description:Candida auris has emerged as a significant healthcare-associated pathogen, posing a serious challenge due to its multidrug-resistant nature. Given the pre-existing constraints in the discovery and provision of new antifungals, there is thus an urgent imperative to design effective strategies to tackle this pressing global concern. Here, we screened a chemical library and identified phenyl-carbohydrazide derivatives with potent activity against both C. auris and the most prevalent human fungal pathogen, C. albicans. SPB00525 (N'-(2,6-Dichlorophenyl)-5-nitro-2-furohydrazide) exhibited potent activity against different strains that were resistant to standard antifungals. Using drug-induced haploinsufficient profiling, transcriptomics and metabolomic analysis, we uncovered that Ole1, a ∆(9) fatty acid desaturase, is most likely the target of SPB00525. We also found that another SPB00525 analog, HTS06170 (N'-(2,6-Dichlorophenyl)-4-methyl-1,2,3-thiadiazole-5-carbohydrazide) had a superior antifungal activity against both C. auris and C. albicans. Both SPB00525 and HTS06170 act as antivirulence agents and inhibited the invasive hyphal growth and biofilm formation of C. albicans. SPB00525 and HTS06170 attenuated fungal damage to human enterocytes and ameliorate survival of Galleria mellonella larvae used as a model of systemic candidiasis. These data, suggest that inhibiting ∆(9) fatty acid desaturase activity represents a potential therapeutic approach for treating fungal infection caused by the superbug C. auris and the most prevalent human fungal pathogen, C. albicans.