Comparing Selection on S. aureus between Antimicrobial Peptides and Common Antibiotics

Abstract

With a diminishing number of effective antibiotics, there has been interest in developing antimicrobial peptides (AMPs) as drugs. However, any new drug faces potential bacterial resistance evolution. Here, we experimentally compare resistance evolution in Staphylococcus aureus selected by three AMPs (from mammals, amphibians and insects), a combination of two AMPs, and two antibiotics: the powerful last-resort vancomycin and the classic streptomycin. We find that resistance evolves readily against single AMPs and against streptomycin, with no detectable fitness cost. However the response to selection from our combination of AMPs led to extinction, in a fashion qualitatively similar to vancomycin. This is consistent with the hypothesis that simultaneous release of multiple AMPs during immune responses is a factor which constrains evolution of AMP resistant pathogens.

Genomic signatures of experimental adaptation to antimicrobial peptides inStaphylococcus aureus

“…Strains were isolated from populations which were created by selecting S. aureus JLA513 9 (hlalacZ hla+, derived from SH1000, from Simon Foster, University of Sheffield) for 28 days with increasing concentrations of AMPs or with the aminoglycoside antibiotic streptomycin 6 . Streptomycin-selected strains are included here as a positive control since the genetic basis of streptomycin resistance is well-characterized in S. aureus.…”

“…The concentrations of the selective agents were doubled each week for a total of four weeks. See Dobson et al 2013 Table S1 for full details and precise concentrations 6 . Strains were isolated from each of three independently selected replicate populations per selective agent (with the exception of iseganan-selected populations where only 2 frozen population stocks remained viable), as well as from unselected controls and the ancestral strain JLA513.…”

“…Current research on AMPs mostly focuses on the mechanisms of action and on the development of therapeutics whereas only a small number of studies have addressed the important problem of bacterial resistance evolution. Resistance against cationic AMPs evolves readily in vitro in Escherichia coli and Pseudomonas aeruginosa 3 , Salmonella enterica 4 , and Staphylococcus aureus 5,6 . Experimentally evolved strains of S. aureus that were selected successfully for resistance against the catioinc protegrin-1 analog iseganan increased survival in the host 7 .…”

“…Experimentally evolved strains of S. aureus that were selected successfully for resistance against the catioinc protegrin-1 analog iseganan increased survival in the host 7 . Here we present a genomic analysis of S. aureus strains from these populations 6 together with susceptibility data from transposon insertion mutants that show a number of the identified genes are directly involved in mediating AMP susceptibility.…”

Perspectives on the evolutionary ecology of arthropod antimicrobial peptides

“…However, experimental evolution studies have repeatedly shown that AMP resistance evolves readily in vitro [105,106]. Interestingly, the evolution of resistance to AMPs seems more difficult if these are acting in combination, that is, in synergy as discussed above [107]. However, this finding deserves more attention.…”