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Antimicrob Agents Chemother. 2014 Sep;58(9):5136-45. doi: 10.1128/AAC.02955-14. Epub 2014 Jun 16.

Comparative mechanistic studies of brilacidin, daptomycin, and the antimicrobial peptide LL16.

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  • 1Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
  • 2PolyMedix Inc., Radnor, Pennsylvania, USA.
  • 3Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA William.DeGrado@ucsf.edu.

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.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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