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

January 5, 2017 at 4:06 pm

Journal of Antimicrobial & Chemotherapy January 1, 2017 V.72 N.1 P.115-127

Jessica Z. Kubicek-Sutherland, Hava Lofton, Martin Vestergaard, Karin Hjort, Hanne Ingmer, and Dan I. Andersson

1Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 75123, Uppsala, Sweden

2Department of Veterinary Disease Biology, University of Copenhagen, Stigbøjlen 4, 1870 Frederiksberg C, Copenhagen, Denmark

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.

PDF

http://jac.oxfordjournals.org/content/72/1/115.full.pdf+html

Entry filed under: Antimicrobianos, Bacterias, Bacteriemias, Biología Molecular, Epidemiología, Resistencia bacteriana, Sepsis, Update. Tags: .

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