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Comparative mechanistic studies of brilacidin, daptomycin, and the antimicrobial peptide LL16.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2014 Sep; Vol. 58 (9), pp. 5136-45. Date of Electronic Publication: 2014 Jun 16. - Publication Year :
- 2014
-
Abstract
- Brilacidin (PMX30063) has shown potent bactericidal activity against drug-resistant and -susceptible strains of multiple Gram-negative and Gram-positive pathogens. In this study, we demonstrate that brilacidin causes membrane depolarization in the Gram-positive bacterium Staphylococcus aureus, to an extent comparable to that caused by the lipopeptidic drug daptomycin. Transcriptional profiling of Staphylococcus aureus by deep sequencing shows that the global response to brilacidin treatment is well correlated to those of treatment with daptomycin and the cationic antimicrobial peptide LL37 and mostly indicates abrogation of cell wall and membrane functions. Furthermore, the upregulation of various chaperones and proteases by brilacidin and daptomycin indicates that cytoplasmic protein misfolding stress may be a contributor to the mechanism of action of these drugs. These stress responses were orchestrated mainly by three two-component systems, GraSR, VraSR, and NsaSR, which have been implicated in virulence and drug resistance against other clinically available antibiotics.<br /> (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- Anti-Bacterial Agents pharmacology
Antimicrobial Cationic Peptides
Bacterial Proteins genetics
Bacterial Proteins metabolism
Cathelicidins pharmacology
Cell Wall genetics
Cell Wall metabolism
Cytoplasm genetics
Cytoplasm metabolism
Microbial Sensitivity Tests
Staphylococcus aureus drug effects
Staphylococcus aureus genetics
Staphylococcus aureus metabolism
Transcription, Genetic genetics
Virulence genetics
Anti-Infective Agents pharmacology
Daptomycin pharmacology
Guanidines pharmacology
Peptides pharmacology
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 58
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 24936592
- Full Text :
- https://doi.org/10.1128/AAC.02955-14