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Multi-Omics Elucidation of Cyclic Lipopeptide Pseudodesmin A-Mediated Biofilm eradication in Vancomycin-Resistant Enterococcus faecalis

ABSTRACT: In this study, we isolated and purified cyclic lipopeptide PDMA from our in-house strain Pseudomonas tolaasii ZTB4. We evaluated its antibacterial and antibiofilm activities against VREF, demonstrating that PDMA effectively eradicates mature biofilms. To decipher the mechanisms underlying this eradication, we employed an integrated multi-omics approach combining transcriptomics, proteomics, and metabolomics to identify key intracellular targets. This represents the first study to investigate the antibiofilm mechanism of PDMA using multi-omics analysis, along with hemolytic assay to evaluate biosafety for future structure-activity relationship analysis. Our findings highlight PDMA as a promising scaffold, underscoring its potential for structural optimization and application in combating biofilm-related drug tolerance.

ORGANISM(S): Enterococcus Faecalis R508

SUBMITTER: Kailing Wang

PROVIDER: PXD079250 | iProX | Thu Jun 04 00:00:00 BST 2026

REPOSITORIES: iProX

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Project description:The success of Enterococcus faecium and E. faecalis evolving as multi-resistant nosocomial pathogens is associated with their ability to acquire and share adaptive traits, including mobile genetic elements (MGE) encoding antimicrobial resistance. Here, we define the mobilome in representative successful hospital associated genetic lineages, E. faecium ST17 (n=10) and ST78 (n=10), E. faecalis ST6 (n=10) and ST40 (n=10) using DNA microarray analyses. The hybridization patterns of 272 targets representing plasmid backbones (n=85), transposable elements (n=85), resistance determinants (n=67), prophages (n=29), and CRISPR-cas sequences (n=6) separated the strains according to species, and for E. faecalis also according to STs. Although plasmids belonging to the RCR-, Rep_3-, RepA_N- and Inc18-families were well represented with no significant differences in prevalence, the presence of specific replicon classes differed highly between the species; E. faecium was dominated by rep17/pRUM, rep2/pRE25, rep14/EFNP1 and rep20/pLG1 and E. faecalis by rep9/pCF10, rep2/pRE25 and rep7. Tn916-elements conferring tetracycline resistance (tetM) were found in all E. faecalis strains, but only in two E. faecium strains. A significant higher prevalence of IS256-, IS3-, ISL3-, IS200/IS605-, IS110-, IS982-, and IS4-transposases were detected in E. faecium, and of IS110-, IS982- and IS1182-transposases in E. faecalis ST6 compared to ST40. Notably, the transposases of IS981, ISEfm1 and IS1678 which have only been reported in few enterococcal isolates, were well represented in the E. faecium strains. E. faecalis ST40 strains harboured possible functional CRISPR-Cas systems, and still resistance and prophage sequences were generally well represented. Gene targets defined as the enterococcal mobilome, including plasmids, IS elements and transposons, resistance determinants, prophage sequences and CRISPR-Cas systems were highly prevalent, underlining their potential importance in the evolution of hospital associated STs. An association between axe-txe to the RepA_N-family and ω-ε-ζ to the Inc18-family, implicates the contribution of TA-systems in stable plasmid maintenance carrying virulence and resistance determinants in enterococci. The concurrent presence of defined MGE and their associated resistance markers was generally confirmed and illustrates the importance of horizontal gene transfer in the development of multidrug resistant enterococci.

Dataset Information

Multi-Omics Elucidation of Cyclic Lipopeptide Pseudodesmin A-Mediated Biofilm eradication in Vancomycin-Resistant Enterococcus faecalis

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