Skip to main content
SpringerLink
Log in
Book cover

Antimicrobial Peptides pp 241–255Cite as

Application of Synthetic Molecular Evolution to the Discovery of Antimicrobial Peptides

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1117))

Abstract

Despite long-standing promise and many known examples, antimicrobial peptides (AMPs) have failed, with few exceptions, to significantly impact human medicine. Impediments to the systemic activity of AMPs include proteolysis, host cell interactions, and serum protein binding, factors that are not often considered in the early stages of AMP development. Here we discuss how synthetic molecular evolution, iterative cycles of library design, and physiologically relevant screening can be used to evolve AMPs that do not have these impediments.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Agawa Y et al (1991) Interaction with phospholipid bilayers, ion channel formation, and antimicrobial activity of basic amphipathic a-helical model peptides of various chain lengths. J Biol Chem 266:20218–20222

    CAS  PubMed  Google Scholar 

  • Arias CA, Murray BE (2009) Antibiotic-resistant bugs in the 21st century – a clinical super-challenge. N Engl J Med 360:439–443

    Article  CAS  Google Scholar 

  • Boucher HW et al (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48:1–12

    Article  Google Scholar 

  • Centers For Disease Control (2014) Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf.

  • Chen CL, Strop P, Lebl M, Lam KS (1996) One bead-one compound combinatorial peptide library: different types of screening. Methods Enzymol 267:211–219

    Article  CAS  Google Scholar 

  • de Breij A et al (2018) The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms. Sci Transl Med 10(423):eaan4044

    Google Scholar 

  • Deuss PJ, Arzumanov A, Williams DL, Gait MJ (2013) Parallel synthesis and splicing redirection activity of cell-penetrating peptide conjugate libraries of a PNA cargo. Org Biomol Chem 11:7621–7630

    Article  CAS  Google Scholar 

  • Dobson AJ, Purves J, Kamysz W, Rolff J (2013) Comparing selection on S. aureus between antimicrobial peptides and common antibiotics. PLoS One 8:e76521

    Article  CAS  Google Scholar 

  • Dooley CT et al (1994) An all D-amino acid opioid peptide with central analgesic activity from a combinatorial library. Science 266:2019–2022

    Article  CAS  Google Scholar 

  • Easton DM, Nijnik A, Mayer ML, Hancock RE (2009) Potential of immunomodulatory host defense peptides as novel anti-infectives. Trends Biotechnol 27:582–590

    Article  CAS  Google Scholar 

  • Fedders H, Podschun R, Leippe M (2010) The antimicrobial peptide Ci-MAM-A24 is highly active against multidrug-resistant and anaerobic bacteria pathogenic for humans. Int J Antimicrob Agents 36:264–266

    Article  CAS  Google Scholar 

  • Fjell CD, Hancock RE, Cherkasov A (2007) AMPer: a database and an automated discovery tool for antimicrobial peptides. Bioinformatics 23:1148–1155

    Article  CAS  Google Scholar 

  • Fox JL (2013) Antimicrobial peptides stage a comeback. Nat Biotechnol 31:379–382

    Article  CAS  Google Scholar 

  • Frank R (2002) The SPOT-synthesis technique. synthetic peptide arrays on membrane supports – principles and applications. J Immunol Methods 267:13–26

    Article  CAS  Google Scholar 

  • Gordon YJ, Romanowski EG, McDermott AM (2005) A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs. Curr Eye Res 30:505–515

    Article  CAS  Google Scholar 

  • Hamill P, Brown K, Jenssen H, Hancock RE (2008) Novel anti-infectives: is host defence the answer? Curr Opin Biotechnol 19:628–636

    Article  CAS  Google Scholar 

  • He L, Hoffmann AR, Serrano C, Hristova K, Wimley WC (2011) High-throughput selection of transmembrane sequences that enhance receptor tyrosine kinase activation. J Mol Biol 412:43–54

    Article  CAS  Google Scholar 

  • He J et al (2013) Direct cytosolic delivery of polar cargo to cells by spontaneous membrane-translocating peptides. J Biol Chem 288:29974–29986

    Article  CAS  Google Scholar 

  • Hilpert K, Volkmer-Engert R, Walter T, Hancock RE (2005) High-throughput generation of small antibacterial peptides with improved activity. Nat Biotechnol 23:1008–1012

    Article  CAS  Google Scholar 

  • Humet M et al (2003) A positional scanning combinatorial library of peptoids as a source of biological active molecules: identification of antimicrobials. J Comb Chem 5:597–605

    Article  CAS  Google Scholar 

  • Joly V, Jidar K, Tatay M, Yeni P (2010) Enfuvirtide: from basic investigations to current clinical use. Expert Opin Pharmacother 11:2701–2713

    Article  CAS  Google Scholar 

  • Kauffman WB, Guha S, Wimley WC (2018) Synthetic molecular evolution of hybrid cell penetrating peptides. Nat Commun 9:2568

    Article  Google Scholar 

  • Kazemzadeh-Narbat M et al (2010) Antimicrobial peptides on calcium phosphate-coated titanium for the prevention of implant-associated infections. Biomaterials 31:9519–9526

    Article  CAS  Google Scholar 

  • Krauson AJ, He J, Wimley WC (2012) Gain-of-function analogues of the pore-forming peptide melittin selected by orthogonal high-throughput screening. J Am Chem Soc 134:12732–12741

    Article  CAS  Google Scholar 

  • Krauson AJ, He J, Hoffmann AR, Wimley AW, Wimley WC (2013) Synthetic molecular evolution of pore-forming peptides by iterative combinatorial library screening. ACS Chem Biol 8:823–831

    Article  CAS  Google Scholar 

  • Krauson AJ et al (2015) Conformational fine-tuning of pore-forming peptide potency and selectivity. J Am Chem Soc 137:16144–16152

    Article  CAS  Google Scholar 

  • Kulagina NV, Shaffer KM, Anderson GP, Ligler FS, Taitt CR (2006) Antimicrobial peptide-based array for Escherichia coli and Salmonella screening. Anal Chim Acta 575:9–15

    Article  CAS  Google Scholar 

  • Kulagina NV, Shaffer KM, Ligler FS, Taitt CR (2007) Antimicrobial peptides as new recognition molecules for screening challenging species. Sensors Actuators B Chem 121:150–157

    Article  CAS  Google Scholar 

  • LaBonte J, Lebbos J, Kirkpatrick P (2003) Enfuvirtide. Nat Rev Drug Discov 2:345–346

    Article  CAS  Google Scholar 

  • Lam KS et al (1991) A new type of synthetic peptide library for identifying ligand-binding activity. Nature (London) 354:82–84

    Article  CAS  Google Scholar 

  • Li S et al (2018) Potent macromolecule-sized poration of lipid bilayers by the Macrolittins, a synthetically evolved family of pore-forming peptides. J Am Chem Soc 140:6441–6447

    Article  CAS  Google Scholar 

  • Marks JR, Placone J, Hristova K, Wimley WC (2011) Spontaneous membrane-translocating peptides by orthogonal high-throughput screening. J Am Chem Soc 133:8995–9004

    Article  CAS  Google Scholar 

  • Mechkarska M et al (2013) An analog of the host-defense peptide hymenochirin-1B with potent broad-spectrum activity against multidrug-resistant bacteria and immunomodulatory properties. Peptides 50:153–159

    Article  CAS  Google Scholar 

  • Molhoek EM, van Dijk A, Veldhuizen EJ, Haagsman HP, Bikker FJ (2011) Improved proteolytic stability of chicken cathelicidin-2 derived peptides by D-amino acid substitutions and cyclization. Peptides 32:875–880

    Article  CAS  Google Scholar 

  • Moy TI et al (2009) High-throughput screen for novel antimicrobials using a whole animal infection model. ACS Chem Biol 4:527–533

    Article  CAS  Google Scholar 

  • Nguyen LT et al (2010) Serum stabilities of short tryptophan- and arginine-rich antimicrobial peptide analogs. PLoS One 5:e12684

    Article  Google Scholar 

  • Okada M, Natori S (1983) Purification and characterization of an antibacterial protein from haemolymph of Sarcophaga peregrina (flesh-fly) larvae. Biochem J 211:727–734

    Article  CAS  Google Scholar 

  • Otto M (2012) MRSA virulence and spread. Cell Microbiol 14:1513–1521

    Article  CAS  Google Scholar 

  • Park SC et al (2011) Synthetic diastereomeric-antimicrobial peptide: antibacterial activity against multiple drug-resistant clinical isolates. Biopolymers 96:130–136

    Article  CAS  Google Scholar 

  • Patterson-Delafield J, Szklarek D, Martinez RJ, Lehrer RI (1981) Microbicidal cationic proteins of rabbit alveolar macrophages: amino acid composition and functional attributes. Infect Immun 31:723–731

    CAS  PubMed  PubMed Central  Google Scholar 

  • Perron GG, Zasloff M, Bell G (2006) Experimental evolution of resistance to an antimicrobial peptide. Proc Biol Sci 273:251–256

    Article  CAS  Google Scholar 

  • Peschel A (2002) How do bacteria resist human antimicrobial peptides? Trends Microbiol 10:179–186

    Article  CAS  Google Scholar 

  • Peschel A, Sahl HG (2006) The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Microbiol 4:529–536

    Article  CAS  Google Scholar 

  • Pollard JE et al (2012) In vitro evaluation of the potential for resistance development to ceragenin CSA-13. J Antimicrob Chemother 67:2665–2672

    Article  CAS  Google Scholar 

  • Poveda E, Briz V, Soriano V (2005) Enfuvirtide, the first fusion inhibitor to treat HIV infection. AIDS Rev 7:139–147

    PubMed  Google Scholar 

  • Qureshi NM, Coy DH, Garry RF, Henderson LA (1990) Characterization of a putative cellular receptor for HIV-1 transmembrane glycoprotein using synthetic peptides. AIDS 4:553–558

    Article  CAS  Google Scholar 

  • Rapaport D, Ovadia M, Shai Y (1995) A synthetic peptide corresponding to a conserved heptad repeat domain is a potent inhibitor of Sendai virus-cell fusion: an emerging similarity with functional domains of other viruses. EMBO J 14:5524–5531

    Article  CAS  Google Scholar 

  • Rathinakumar R, Wimley WC (2008) Biomolecular engineering by combinatorial design and high-throughput screening: small, soluble peptides that permeabilize membranes. J Am Chem Soc 130:9849–9858

    Article  CAS  Google Scholar 

  • Rathinakumar R, Wimley WC (2010) High-throughput discovery of broad-spectrum peptide antibiotics. FASEB J 24:3232–3238

    Article  CAS  Google Scholar 

  • Rathinakumar R, Walkenhorst WF, Wimley WC (2009) Broad-spectrum antimicrobial peptides by rational combinatorial design and high-throughput screening: the importance of interfacial activity. J Am Chem Soc 131:7609–7617

    Article  CAS  Google Scholar 

  • Rausch JM, Marks JR, Wimley WC (2005) Rational combinatorial design of pore-forming beta-sheet peptides. Proc Natl Acad Sci U S A 102:10511–10515

    Article  CAS  Google Scholar 

  • Riedl S, Zweytick D, Lohner K (2011a) Membrane-active host defense peptides – challenges and perspectives for the development of novel anticancer drugs. Chem Phys Lipids 164:766–781

    Article  CAS  Google Scholar 

  • Riedl S et al (2011b) In search of a novel target – phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy. Biochim Biophys Acta 1808:2638–2645

    Article  CAS  Google Scholar 

  • Savini F et al (2017) Cell-density dependence of host-defense peptide activity and selectivity in the presence of host cells. ACS Chem Biol 12:52–56

    Article  CAS  Google Scholar 

  • Savini F, Bobone S, Roversi D, Mangoni M, Stella L (2018) From liposomes to cells: filling the gap between physicochemical and microbiological studies of the activity and selectivity of host-defense peptides. Pept Sci 110:e24041

    Article  Google Scholar 

  • Schlusselhuber M et al (2014) In vitro effectiveness of the antimicrobial peptide eCATH1 against antibiotic-resistant bacterial pathogens of horses. FEMS Microbiol Lett 350:216–222

    Article  CAS  Google Scholar 

  • Selsted ME, Brown DM, DeLange RJ, Harwig SSL, Lehrer RI (1985) Primary structures of six antimicrobial peptides of rabbit peritoneal neutrophils. J Biol Chem 260:4579–4584

    CAS  Google Scholar 

  • Starr CG, Wimley WC (2017) Antimicrobial peptides are degraded by the cytosolic proteases of human erythrocytes. Biochim Biophys Acta 1859:2319–2326

    Article  CAS  Google Scholar 

  • Starr CG, He J, Wimley WC (2016) Host cell interactions are a significant barrier to the clinical utility of peptide antibiotics. ACS Chem Biol 11:3391–3399

    Article  CAS  Google Scholar 

  • Starr CG, Maderdrut JL, He J, Coy DH, Wimley WC (2018) Pituitary adenylate cyclase-activating polypeptide is a potent broad-spectrum antimicrobial peptide: structure-activity relationships. Peptides 104:35–40

    Article  CAS  Google Scholar 

  • Steiner H, Hultmark D, Engstrom A, Bennich H, Boman HG (1981) Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature (London) 292:246–248

    Article  CAS  Google Scholar 

  • Steiner H, Andreu D, Merrifield RB (1988) Binding and action of cecropin and cecropin analogues: antibacterial peptides from insects. Biochim Biophys Acta 939:260–266

    Article  CAS  Google Scholar 

  • Tran D et al (2002) Homodimeric theta-defensins from rhesus macaque leukocytes: isolation, synthesis, antimicrobial activities, and bacterial binding properties of the cyclic peptides. J Biol Chem 277:3079–3084

    Article  CAS  Google Scholar 

  • Wang G, Li X, Wang Z (2016) APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res 44:D1087–D1093

    Article  CAS  Google Scholar 

  • Werle M, Bernkop-Schnurch A (2006) Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids 30:351–367

    Article  CAS  Google Scholar 

  • Wiedman G, Kim SY, Zapata-Mercado E, Wimley WC, Hristova K (2016) PH-triggered, macromolecule-sized poration of lipid bilayers by synthetically evolved peptides. J Am Chem Soc 139:937–945

    Article  Google Scholar 

  • Wimley WC (2010) Describing the mechanism of antimicrobial peptide action with the interfacial activity model. ACS Chem Biol 5:905–917

    Article  CAS  Google Scholar 

  • Wolfmeier H, Pletzer D, Mansour SC, Hancock REW (2017) New perspectives in biofilm eradication. ACS Infect Dis 4:93–106

    Article  Google Scholar 

  • Yeaman MR, Yount NY (2003) Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev 55:27–55

    Article  CAS  Google Scholar 

  • Zasloff M (1987) Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc Natl Acad Sci U S A 84:5449–5453

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, USA

    William C. Wimley

Authors
  1. William C. Wimley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William C. Wimley .

Editor information

Editors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan

    Katsumi Matsuzaki

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wimley, W.C. (2019). Application of Synthetic Molecular Evolution to the Discovery of Antimicrobial Peptides. In: Matsuzaki, K. (eds) Antimicrobial Peptides. Advances in Experimental Medicine and Biology, vol 1117. Springer, Singapore. https://doi.org/10.1007/978-981-13-3588-4_13

Download citation

Publish with us

Policies and ethics

Search

Navigation