title: Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 75123, Uppsala, Sweden.
authors.forename: Jessica Z
authors.initials: JZ
authors.lastname: Kubicek-Sutherland
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 75123, Uppsala, Sweden.
authors.forename: Hava
authors.initials: H
authors.lastname: Lofton
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Stigbøjlen 4, 1870 Frederiksberg C, Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Vestergaard
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 75123, Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Hjort
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Stigbøjlen 4, 1870 Frederiksberg C, Copenhagen, Denmark.
authors.forename: Hanne
authors.initials: H
authors.lastname: Ingmer
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 75123, Uppsala, Sweden dan.andersson@imbim.uu.se.
authors.forename: Dan I
authors.initials: DI
authors.lastname: Andersson
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity; D008807:Mice, Inbred BALB C; D012641:Selection, Genetic; D018805:Sepsis / Q000382:microbiology / Q000473:pathology; D012692:Serial Passage; D013203:Staphylococcal Infections / Q000382:microbiology / Q000473:pathology; D014774:Virulence
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides