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Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides

BACKGROUND: The clinical development of antimicrobial peptides (AMPs) is currently under evaluation to combat the rapid increase in MDR bacterial pathogens. However, many AMPs closely resemble components of the human innate immune system and the ramifications of prolonged bacterial exposure to AMPs...

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Autores principales: Kubicek-Sutherland, Jessica Z., Lofton, Hava, Vestergaard, Martin, Hjort, Karin, Ingmer, Hanne, Andersson, Dan I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161045/
https://www.ncbi.nlm.nih.gov/pubmed/27650186
http://dx.doi.org/10.1093/jac/dkw381
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author Kubicek-Sutherland, Jessica Z.
Lofton, Hava
Vestergaard, Martin
Hjort, Karin
Ingmer, Hanne
Andersson, Dan I.
author_facet Kubicek-Sutherland, Jessica Z.
Lofton, Hava
Vestergaard, Martin
Hjort, Karin
Ingmer, Hanne
Andersson, Dan I.
author_sort Kubicek-Sutherland, Jessica Z.
collection PubMed
description BACKGROUND: The clinical development of antimicrobial peptides (AMPs) is currently under evaluation to combat the rapid increase in MDR bacterial pathogens. However, many AMPs closely resemble components of the human innate immune system and the ramifications of prolonged bacterial exposure to AMPs are not fully understood. OBJECTIVES: We show that in vitro serial passage of a clinical USA300 MRSA strain in a host-mimicking environment containing host-derived AMPs results in the selection of stable AMP resistance. METHODS: Serial passage experiments were conducted using steadily increasing concentrations of LL-37, PR-39 or wheat germ histones. WGS and proteomic analysis by MS were used to identify the molecular mechanism associated with increased tolerance of AMPs. AMP-resistant mutants were characterized by measuring in vitro fitness, AMP and antibiotic susceptibility, and virulence in a mouse model of sepsis. RESULTS: AMP-resistant Staphylococcus aureus mutants often displayed little to no fitness cost and caused invasive disease in mice. Further, this phenotype coincided with diminished susceptibility to both clinically prescribed antibiotics and human defence peptides. CONCLUSIONS: These findings suggest that therapeutic use of AMPs could select for virulent mutants with cross-resistance to human innate immunity as well as antibiotic therapy. Thus, therapeutic use of AMPs and the implications of cross-resistance need to be carefully monitored and evaluated.
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spelling pubmed-51610452016-12-19 Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides Kubicek-Sutherland, Jessica Z. Lofton, Hava Vestergaard, Martin Hjort, Karin Ingmer, Hanne Andersson, Dan I. J Antimicrob Chemother Original Research BACKGROUND: The clinical development of antimicrobial peptides (AMPs) is currently under evaluation to combat the rapid increase in MDR bacterial pathogens. However, many AMPs closely resemble components of the human innate immune system and the ramifications of prolonged bacterial exposure to AMPs are not fully understood. OBJECTIVES: We show that in vitro serial passage of a clinical USA300 MRSA strain in a host-mimicking environment containing host-derived AMPs results in the selection of stable AMP resistance. METHODS: Serial passage experiments were conducted using steadily increasing concentrations of LL-37, PR-39 or wheat germ histones. WGS and proteomic analysis by MS were used to identify the molecular mechanism associated with increased tolerance of AMPs. AMP-resistant mutants were characterized by measuring in vitro fitness, AMP and antibiotic susceptibility, and virulence in a mouse model of sepsis. RESULTS: AMP-resistant Staphylococcus aureus mutants often displayed little to no fitness cost and caused invasive disease in mice. Further, this phenotype coincided with diminished susceptibility to both clinically prescribed antibiotics and human defence peptides. CONCLUSIONS: These findings suggest that therapeutic use of AMPs could select for virulent mutants with cross-resistance to human innate immunity as well as antibiotic therapy. Thus, therapeutic use of AMPs and the implications of cross-resistance need to be carefully monitored and evaluated. Oxford University Press 2017-01 2016-09-20 /pmc/articles/PMC5161045/ /pubmed/27650186 http://dx.doi.org/10.1093/jac/dkw381 Text en © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Research
Kubicek-Sutherland, Jessica Z.
Lofton, Hava
Vestergaard, Martin
Hjort, Karin
Ingmer, Hanne
Andersson, Dan I.
Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides
title Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides
title_full Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides
title_fullStr Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides
title_full_unstemmed Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides
title_short Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides
title_sort antimicrobial peptide exposure selects for staphylococcus aureus resistance to human defence peptides
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161045/
https://www.ncbi.nlm.nih.gov/pubmed/27650186
http://dx.doi.org/10.1093/jac/dkw381
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