Drug Resistance Updates 26 (2016) 43–57 Contents lists available at ScienceDirect Drug Resistance Updates jo urnal homepage: www.elsevier.com/locate/drup Invited review Mechanisms and consequences of bacterial resistance to antimicrobial peptides ∗ D.I. Andersson , D. Hughes, J.Z. Kubicek-Sutherland Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, SE-751 23 Uppsala, Sweden a r t i c l e i n f o a b s t r a c t Article history: Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over Received 14 March 2016 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the Received in revised form 7 April 2016 increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an Accepted 11 April 2016 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 Keywords: aimed at modulating the expression of AMPs to boost the human innate immune response. In this review Antimicrobial peptides we discuss the potential problems associated with these therapeutic approaches. There is considerable Anti-bacterial drugs Resistance 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 Innate immunity Selection of bacteria in a natural setting will be determined by a complex interplay of several different factors, Bacterial infections 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 bac- terial 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. © 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction to AMPs . 44 1.1. Definition of AMPs and early history . 44 2. Structures of AMPs . 44 3. AMP structure influences activity . 45 4. Biological roles of AMPs . 45 4.1. Expression of AMPs . 45 4.2. Antibacterial activity (direct) . 45 4.3. Immune modulation (may indirectly be antibacterial) . 45 5. Mode of action of AMPs . 45 5.1. Membrane interaction specificity . 45 5.2. Membrane and cell wall activity of AMPs . 46 5.3. AMPs activity may also involve intracellular targets . 46 6. Intrinsic resistance to AMPs . 46 6.1. Membrane modifications in Gram-negative bacteria . 46 6.2. Membrane modifications in Gram-positive bacteria . 47 6.3. Other intrinsic AMP resistance mechanisms . 47 6.4. Methods to identify intrinsic AMP resistance mechanisms . 48 ∗ Corresponding author. Tel.: +46 18 4714175. E-mail address: [email protected] (D.I. Andersson). http://dx.doi.org/10.1016/j.drup.2016.04.002 1368-7646/© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). 44 D.I. Andersson et al. / Drug Resistance Updates 26 (2016) 43–57 7. Acquired resistance . 48 7.1. Methods to select for mutants with acquired AMP resistance . 48 7.2. Mechanisms of acquired resistance . 49 7.2.1. Naturally occurring acquired resistance . 49 7.2.2. Serial passage . 50 7.2.3. Direct plating . 50 7.3. What determines the risk of acquiring resistance to AMPs? . 51 7.3.1. Mutation supply rate . 51 7.3.2. Mutant fitness . 51 7.3.3. Selection strength . 52 7.3.4. Compensatory evolution . ..