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Context Mediates Antimicrobial Efficacy of Kinocidin Congener Peptide RP-1

Yount, Nannette Y. and Cohen, Samuel E. and Kupferwasser, Deborah and Waring, Alan J. and Ruchala, Piotr and Sharma, Shantanu and Wasserman, Karlman and Jung, Chun-Ling and Yeaman, Michael R. (2011) Context Mediates Antimicrobial Efficacy of Kinocidin Congener Peptide RP-1. PLoS ONE, 6 (11). Art. No. e26727. ISSN 1932-6203. PMCID PMC3208557.

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Structure-mechanism relationships are key determinants of host defense peptide efficacy. These relationships are influenced by anatomic, physiologic and microbiologic contexts. Structure-mechanism correlates were assessed for the synthetic peptide RP-1, modeled on microbicidal domains of platelet kinocidins. Antimicrobial efficacies and mechanisms of action against susceptible (^S) or resistant (^R) Salmonella typhimurium (ST), Staphylococcus aureus (SA), and Candida albicans (CA) strain pairs were studied at pH 7.5 and 5.5. Although RP-1 was active against all study organisms, it exhibited greater efficacy against bacteria at pH 7.5, but greater efficacy against CA at pH 5.5. RP-1 de-energized SA and CA, but caused hyperpolarization of ST in both pH conditions. However, RP-1 permeabilized ST^S and CA strains at both pH, whereas permeabilization was modest for ST^R or SA strain at either pH. Biochemical analysis, molecular modeling, and FTIR spectroscopy data revealed that RP-1 has indistinguishable net charge and backbone trajectories at pH 5.5 and 7.5. Yet, concordant with organism-specific efficacy, surface plasmon resonance, and FTIR, molecular dynamics revealed modest helical order increases but greater RP-1 avidity and penetration of bacterial than eukaryotic lipid systems, particularly at pH 7.5. The present findings suggest that pH– and target–cell lipid contexts influence selective antimicrobial efficacy and mechanisms of RP-1 action. These findings offer new insights into selective antimicrobial efficacy and context–specificity of antimicrobial peptides in host defense, and support design strategies for potent anti-infective peptides with minimal concomitant cytotoxicity.

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Additional Information:© 2011 Yount et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: April 19, 2011; Accepted: October 2, 2011; Published: November 4, 2011. We gratefully acknowledge the University of California, Irvine Office of Information Technology, and the Broadcom Corporation for underwriting the Broadcom Distributed / Unified Cluster (BDUC) platform upon which the GROMACS molecular dynamics simulations were performed. We appreciate Harry Mangalam for excellent technical assistance in optimizing the molecular dynamics experiments. We thank David Poger for assistance in optimizing parameter specifications for POPE. We are grateful to Mei Hong for helpful review of the manuscript. Author Contributions: Conceived and designed the experiments: NY SC AW MY. Performed the experiments: NY SC DK AW PR C-IJ. Analyzed the data: NY SC AW KW SS MY. Contributed reagents/materials/analysis tools: AW SS. Wrote the paper: NY SC AW MY. This study was supported in-part by National Institute of Health grants AI-39001 and AI-48031 (MY). No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist.
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Issue or Number:11
PubMed Central ID:PMC3208557
Record Number:CaltechAUTHORS:20200218-151248491
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Official Citation:Yount NY, Cohen SE, Kupferwasser D, Waring AJ, Ruchala P, Sharma S, et al. (2011) Context Mediates Antimicrobial Efficacy of Kinocidin Congener Peptide RP-1. PLoS ONE 6(11): e26727.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101338
Deposited By: George Porter
Deposited On:19 Feb 2020 18:18
Last Modified:19 Feb 2020 18:18

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