Genomic Signatures of Experimental Adaptation to Antimicrobial Peptides in Staphylococcus aureus

The evolution of resistance against antimicrobial peptides has long been considered unlikely due to their mechanism of action, yet experimental selection with AMPs results in rapid evolution of resistance in several species of bacteria. Although numerous studies have utilized mutant screens to identify loci that determine AMP susceptibility, there is a dearth of data concerning the genomic changes which accompany experimental evolution of AMP resistance. Using genome re-sequencing we analysed the mutations which arise during experimental evolution of resistance to the cationic AMPs iseganan, melittin and pexiganan, as well as to a combination of melittin and pexiganan, or to the aminoglycoside antibiotic streptomycin. Analysis of 17 independently replicated Staphylococcus aureus selection lines, including unselected controls, showed that each AMP selected for mutations at distinct loci. We identify mutations in genes involved in the synthesis and maintenance of the cell envelope. This includes genes previously identified from mutant screens for AMP resistance, and genes involved in the response to AMPs and cell-wall-active antibiotics. Furthermore, transposon insertion mutants were used to verify that a number of the identified genes are directly involved in determining AMP susceptibility. Strains selected for AMP resistance under controlled experimental evolution displayed consistent AMP-specific mutations in genes which determine AMP susceptibility. This suggests that different routes to evolve resistance are favored within a controlled genetic background.

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