Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides
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Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides. / Kubicek-Sutherland, Jessica Z.; Lofton, Hava; Vestergaard, Martin; Hjort, Karin ; Ingmer, Hanne; Anderson, Dan I.
I: Journal of Antimicrobial Chemotherapy, Bind 72, Nr. 1, 01.2017, s. 115-127.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides
AU - Kubicek-Sutherland, Jessica Z.
AU - Lofton, Hava
AU - Vestergaard, Martin
AU - Hjort, Karin
AU - Ingmer, Hanne
AU - Anderson, Dan I.
PY - 2017/1
Y1 - 2017/1
N2 - 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 humaninnate 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 experimentswere 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 associatedwith 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 prescribedantibiotics and human defence peptides.Conclusions: These findings suggest that therapeutic use of AMPs could select for virulent mutants with crossresistance 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.
AB - 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 humaninnate 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 experimentswere 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 associatedwith 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 prescribedantibiotics and human defence peptides.Conclusions: These findings suggest that therapeutic use of AMPs could select for virulent mutants with crossresistance 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.
U2 - 10.1093/jac/dkw381
DO - 10.1093/jac/dkw381
M3 - Journal article
C2 - 27650186
VL - 72
SP - 115
EP - 127
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
SN - 0305-7453
IS - 1
ER -
ID: 166158004