title: Mechanisms and consequences of bacterial resistance to antimicrobial peptides.
abstract: Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an alternative antibacterial therapy. Several cationic peptides that are derivatives of AMPs from the human innate immune system are currently in clinical development. There are also ongoing clinical studies aimed at modulating the expression of AMPs to boost the human innate immune response. In this review we discuss the potential problems associated with these therapeutic approaches. There is considerable experimental data describing mechanisms by which bacteria can develop resistance to AMPs. As for any type of drug resistance, the rate by which AMP resistance would emerge and spread in a population of bacteria in a natural setting will be determined by a complex interplay of several different factors, including the mutation supply rate, the fitness of the resistant mutant at different AMP concentrations, and the strength of the selective pressure. Several studies have already shown that AMP-resistant bacterial mutants display broad cross-resistance to a variety of AMPs with different structures and modes of action. Therefore, routine clinical administration of AMPs to treat bacterial infections may select for resistant bacterial pathogens capable of better evading the innate immune system. The ramifications of therapeutic levels of exposure on the development of AMP resistance and bacterial pathogenesis are not yet understood. This is something that needs to be carefully studied and monitored if AMPs are used in clinical settings.
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, SE-751 23 Uppsala, Sweden. Electronic address: Dan.Andersson@imbim.uu.se.
authors.forename: D I
authors.initials: DI
authors.lastname: Andersson
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, SE-751 23 Uppsala, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Hughes
authors.affiliation: Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, SE-751 23 Uppsala, Sweden.
authors.forename: J Z
authors.initials: JZ
authors.lastname: Kubicek-Sutherland
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000276:immunology / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006801:Humans; D007113:Immunity, Innate
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides
keywords: Anti-bacterial drugs; Antimicrobial peptides; Bacterial infections; Innate immunity; Resistance; Selection