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Development of a transcription factor decoy-nanocarrier system as a successful inhibitor of Enterococcus faecalis virulence in vitro and in vivo.
- Source :
-
Microbial pathogenesis [Microb Pathog] 2024 Aug; Vol. 193, pp. 106762. Date of Electronic Publication: 2024 Jun 25. - Publication Year :
- 2024
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Abstract
- Enterococcus faecalis is a troublesome nosocomial pathogen that acquired resistance to most available antimicrobial agents. Antivirulence agents represent an unconventional treatment approach. Here, transcription factor decoy (TFD)-loaded cationic liposomes (TLL) were developed as an inhibitor of the Fsr quorum-sensing system and its associated virulence traits, in E. faecalis. The consensus sequence of the FsrA binding site was found conserved among 651 E. faecalis annotated genomes. The TFD was synthesized as an 82 bp DNA duplex, containing the conserved binding sequence, and loaded onto cationic liposomes. The optimum loading capacity, mean particle size, and zeta potential of the TLL were characterized. The developed TLL lacked any effect on E. faecalis growth and significantly inhibited the in vitro production of the proteolytic enzymes controlled by the Fsr system; gelatinase and serine protease, in a concentration-dependent manner. This inhibition was accompanied by a significant reduction in the transcription levels of FsrA-regulated genes (fsrB, gelE, and sprE). The developed TLL were safe as evidenced by the nonhemolytic effect on human RBCs and the negligible cytotoxicity on human skin fibroblast cells. Moreover, in the larvae infection model, TLL displayed a significant abolish in the mortality rates of Galleria mellonella larvae infected with E. faecalis. In conclusion, the developed TLL offer a new safe strategy for combating E. faecalis infection through the inhibition of quorum-sensing-mediated virulence; providing a platform for the development of similar agents to combat many other pathogens.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Virulence drug effects
Humans
Anti-Bacterial Agents pharmacology
Liposomes
Larva microbiology
Transcription Factors metabolism
Transcription Factors genetics
Virulence Factors genetics
Gelatinases metabolism
Gelatinases antagonists & inhibitors
Moths microbiology
Erythrocytes drug effects
Disease Models, Animal
Serine Proteases metabolism
Serine Proteases genetics
Gene Expression Regulation, Bacterial drug effects
Nanoparticles chemistry
Serine Endopeptidases genetics
Serine Endopeptidases metabolism
Enterococcus faecalis drug effects
Enterococcus faecalis genetics
Quorum Sensing drug effects
Gram-Positive Bacterial Infections microbiology
Gram-Positive Bacterial Infections drug therapy
Bacterial Proteins genetics
Bacterial Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1096-1208
- Volume :
- 193
- Database :
- MEDLINE
- Journal :
- Microbial pathogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 38936638
- Full Text :
- https://doi.org/10.1016/j.micpath.2024.106762