This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Xiong, Y. Q.
Right arrow Articles by Yeaman, M. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xiong, Y. Q.
Right arrow Articles by Yeaman, M. R.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, November 2006, p. 3786-3792, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00038-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Synthetic Congener Modeled on a Microbicidal Domain of Thrombin- Induced Platelet Microbicidal Protein 1 Recapitulates Staphylocidal Mechanisms of the Native Molecule{triangledown}

Yan Q. Xiong,1,2* Arnold S. Bayer,1,2 Lisa Elazegui,1,{dagger} and Michael R. Yeaman1,2

Department of Medicine, Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502,1 David Geffen School of Medicine at UCLA, Los Angeles, California 900242

Received 10 January 2006/ Returned for modification 16 February 2006/ Accepted 23 August 2006

Thrombin-induced platelet microbicidal protein 1 (tPMP-1) is a staphylocidal peptide released by activated platelets. This peptide initiates its microbicidal activity by membrane permeabilization, with ensuing inhibition of intracellular macromolecular synthesis. RP-1 is a synthetic congener modeled on the C-terminal microbicidal {alpha}-helix of tPMP-1. This study compared the staphylocidal mechanisms of RP-1 with those of tPMP-1, focusing on isogenic tPMP-1-susceptible (ISP479C) and -resistant (ISP479R) Staphylococcus aureus strains for the following quantitative evaluations: staphylocidal efficacy; comparative MIC; membrane permeabilization (MP) and depolarization; and DNA, RNA, and protein synthesis. Although the proteins had similar MICs, RP-1 caused significant killing of ISP479C (<50% survival), correlating with extensive MP (>95%) and inhibition of DNA and RNA synthesis (>90%), versus substantially reduced killing of ISP479R (>80% survival), with less MP (55%) and less inhibition of DNA or RNA synthesis (70 to 80%). Interestingly, RP-1-induced protein synthesis inhibition was equivalent in both strains. RP-1 did not depolarize the cell membrane and caused a relatively short postexposure growth inhibition. These data closely parallel those previously reported for tPMP-1 against this strain set and exemplify how synthetic molecules can be engineered to reflect structure-activity relationships of functional domains in native host defense effector molecules.

* Corresponding author. Mailing address: Department of Medicine, Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, RB-2, Room 231, Torrance, CA 90502. Phone: (310) 222-3545. Fax: (310) 782-2016. E-mail: yxiong{at}ucla.edu.

{triangledown} Published ahead of print on 5 September 2006.

{dagger} Present address: Loma Linda University, School of Pharmacy, Loma Linda, CA 92350.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3786-3792, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00038-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Jones, T., Yeaman, M. R., Sakoulas, G., Yang, S.-J., Proctor, R. A., Sahl, H.-G., Schrenzel, J., Xiong, Y. Q., Bayer, A. S. (2008). Failures in Clinical Treatment of Staphylococcus aureus Infection with Daptomycin Are Associated with Alterations in Surface Charge, Membrane Phospholipid Asymmetry, and Drug Binding. Antimicrob. Agents Chemother. 52: 269-278 [Abstract] [Full Text]  
  • Mukhopadhyay, K., Whitmire, W., Xiong, Y. Q., Molden, J., Jones, T., Peschel, A., Staubitz, P., Adler-Moore, J., McNamara, P. J., Proctor, R. A., Yeaman, M. R., Bayer, A. S. (2007). In vitro susceptibility of Staphylococcus aureus to thrombin-induced platelet microbicidal protein-1 (tPMP-1) is influenced by cell membrane phospholipid composition and asymmetry. Microbiology 153: 1187-1197 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»