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Engineered OAKs Against Antibiotic Resistance and for Bacterial Detection

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Host Defense Peptides and Their Potential as Therapeutic Agents

Abstract

As bacterial resistance to antibiotics continues to threaten modern healthcare worldwide, the need for new approaches that control bacterial infections becomes evermore urgent. Membrane-active compounds (MACs) are currently gaining interest for their potential to address various antibiotic resistance challenges. Since MACs are able to target multiple vital bacterial functions simultaneously, they may have the advantage of fighting the infection while avoiding many of the known resistance mechanisms. This chapter reviews current data regarding the attempts to use oligomers of acylated cations (OACs) as a platform for optimizing the hydrophobic/cationic balance required for selective nonspecific membrane interactions of MACs, under in vitro and in vivo conditions. With the perspective gained over nearly a decade after their conception and after a few dozen investigations involving several hundreds of analogs, we describe the properties of a few representative lysyl-based OAC (OAK) sequences. These sequences reflect the OAC concept evolution from the original focus on bactericidal MACs that later shifted onto bacteriostatic derivatives and presently concentrates on seemingly inactive analogs that nonetheless improve the control of bacterial infections. Collectively, the current data appear to substantiate the potential of OAC-based MACs as a valuable resource for therapeutic antibacterial development, including for systemic applications.

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References

  • Allen RC, Popat R, Diggle SP, Brown SP (2014) Targeting virulence: can we make evolution-proof drugs? Nat Rev Microbiol 12:300–308

    Article  CAS  PubMed  Google Scholar 

  • Andra J, Goldmann T, Ernst CM, Peschel A, Gutsmann T (2011) Multiple peptide resistance factor (MprF)-mediated resistance of Staphylococcus aureus against antimicrobial peptides coincides with a modulated peptide interaction with artificial membranes comprising lysyl-phosphatidylglycerol. J Biol Chem 286:18692–18700

    Article  PubMed  PubMed Central  Google Scholar 

  • Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ (2015) Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 13:42–51

    Article  CAS  PubMed  Google Scholar 

  • Choi S, Isaacs A, Clements D, Liu D, Kim H, Scott RW, Winkler JD, DeGrado WF (2009) De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers. Proc Natl Acad Sci USA 106:6968–6973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daly SM, Elmore BO, Kavanaugh JS, Triplett KD, Figueroa M, Raja HA, El-Elimat T, Crosby HA, Femling JK, Cech NB, Horswill AR, Oberlies NH, Hall PR (2015) ω-Hydroxyemodin limits staphylococcus aureus quorum sensing-mediated pathogenesis and inflammation. Antimicrob Agents Chemother 59:2223–2235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dhand A, Bayer AS, Pogliano J, Yang SJ, Bolaris M, Nizet V, Wang G, Sakoulas G (2011) Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding. Clin Infect Dis 53:158–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eckert R (2011) Road to clinical efficacy: challenges and novel strategies for antimicrobial peptide development. Future Microbiol 6:635–651

    Article  CAS  PubMed  Google Scholar 

  • Epand RM, Epand RF (2009) Lipid domains in bacterial membranes and the action of antimicrobial agents. Biochim Biophys Acta 1788:289–294

    Article  CAS  PubMed  Google Scholar 

  • Epand RM, Vogel HJ (1999) Diversity of antimicrobial peptides and their mechanisms of action. Biochim Biophys Acta 1462:11–28

    Article  CAS  PubMed  Google Scholar 

  • Epand RM, Rotem S, Mor A, Berno B, Epand RF (2008a) Bacterial membranes as predictors of antimicrobial potency. J Am Chem Soc 130:14346–14352

    Article  CAS  PubMed  Google Scholar 

  • Epand R, Rotem S, Mor A, Berno B, Epand R (2008b) Bacterial membranes as predictors of antimicrobial potency. J Am Chem Soc 130:14346–14352

    Article  CAS  PubMed  Google Scholar 

  • Epand RF, Maloy WL, Ramamoorthy A, Epand RM (2010) Probing the “charge cluster mechanism” in amphipathic helical cationic antimicrobial peptides. Biochemistry 49:4076–4084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Epand RF, Sarig H, Ohana D, Papahadjopoulos-Sternberg B, Mor A, Epand RM (2011) Physical properties affecting cochleate formation and morphology using antimicrobial oligo-acyl-lysyl peptide mimetics and mixtures mimicking the composition of bacterial membranes in the absence of divalent cations. J Phys Chem B 115:2287–2293

    Article  CAS  PubMed  Google Scholar 

  • Fedtke I, Gotz F, Peschel A (2004) Bacterial evasion of innate host defenses-the Staphylococcus aureus lesson. Int J Med Microbiol 294:189–194

    Article  CAS  PubMed  Google Scholar 

  • Fernandez L, Gooderham WJ, Bains M, McPhee JB, Wiegand I, Hancock RE (2010) Adaptive resistance to the “last hope” antibiotics polymyxin B and colistin in Pseudomonas aeruginosa is mediated by the novel two-component regulatory system ParR-ParS. Antimicrob Agents Chemother 54:3372–3382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fischbach MA, Walsh CT (2009) Antibiotics for emerging pathogens. Science 325:1089–1093 (New York, N.Y.)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaidukov L, Fish A, Mor A (2003) Analysis of membrane-binding properties of dermaseptin analogues: relationships between binding and cytotoxicity. Biochemistry 42:12866–12874

    Article  CAS  PubMed  Google Scholar 

  • Goldberg K, Sarig H, Zaknoon F, Epand RF, Epand RM, Mor A (2013) Sensitization of gram-negative bacteria by targeting the membrane potential. FASEB J 27:3818–3826

    Article  CAS  PubMed  Google Scholar 

  • Gooderham WJ, Hancock RE (2009) Regulation of virulence and antibiotic resistance by two-component regulatory systems in Pseudomonas aeruginosa. FEMS Microbiol Rev 33:279–294

    Article  CAS  PubMed  Google Scholar 

  • Hancock RE (2005) Mechanisms of action of newer antibiotics for Gram-positive pathogens. Lancet Infect Dis 5:209–218

    Article  CAS  PubMed  Google Scholar 

  • Hancock RE, Chapple DS (1999) Peptide antibiotics. Antimicrob Agents Chemother 43:1317–1323

    CAS  PubMed  PubMed Central  Google Scholar 

  • Haney EF, Hancock RE (2013) Peptide design for antimicrobial and immunomodulatory applications. Biopolymers 100:572–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Held-Kuznetsov V, Rotem S, Assaraf YG, Mor A (2009) Host-defense peptide mimicry for novel antitumor agents. FASEB J 23:4299–4307

    Article  CAS  PubMed  Google Scholar 

  • Hicks DB, Cohen DM, Krulwich TA (1994) Reconstitution of energy-linked activities of the solubilized F1F0 ATP synthase from Bacillus subtilis. J Bacteriol

    Google Scholar 

  • Hurdle JG, O’Neill AJ, Chopra I, Lee RE (2011) Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat Rev Microbiol 9:62–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iqbal SS, Mayo MW, Bruno JG, Bronk BV, Batt CA, Chambers JP (2000) A review of molecular recognition technologies for detection of biological threat agents. Biosens Bioelectron 15:549–578

    Article  CAS  PubMed  Google Scholar 

  • Jahnsen RD, Haney EF, Franzyk H, Hancock RE (2013) Characterization of a proteolytically stable multifunctional host defense peptidomimetic. Chem Biol 20:1286–1295

    Article  CAS  PubMed  Google Scholar 

  • Jammal J, Zaknoon F, Kaneti G, Goldberg G, Mor A (2015) Sensitization of Gram-negative bacteria to rifampin and OAK combinations. Scientific Reports 5

    Google Scholar 

  • Jean-Francois F, Castano S, Desbat B, Odaert B, Roux M, Metz-Boutigue MH, Dufourc EJ (2008) Aggregation of cateslytin beta-sheets on negatively charged lipids promotes rigid membrane domains. A new mode of action for antimicrobial peptides? Biochemistry 47:6394–6402

    Article  CAS  PubMed  Google Scholar 

  • Kaneti G, Sarig H, Marjieh I, Zaknoon F, Mor A (2013) Simultaneous breakdown of multiple antibiotic resistance mechanisms in S. aureus. FASEB J

    Google Scholar 

  • Kinch MS, Haynesworth A, Kinch SL, Hoyer D (2014) An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov Today 19:1033–1039

    Article  CAS  PubMed  Google Scholar 

  • Klitgaard JK, Skov MN, Kallipolitis BH, Kolmos HJ (2008) Reversal of methicillin resistance in Staphylococcus aureus by thioridazine. J Antimicrob Chemother 62:1215–1221

    Article  CAS  PubMed  Google Scholar 

  • Koprivnjak T, Peschel A (2011) Bacterial resistance mechanisms against host defense peptides. Cell Mol Life Sci 68:2243–2254

    Article  CAS  PubMed  Google Scholar 

  • Li SA, Liu J, Xiang Y, Wang YJ, Lee WH, Zhang Y (2014) Therapeutic potential of the antimicrobial peptide OH-CATH30 for antibiotic-resistant Pseudomonas aeruginosa keratitis. Antimicrob Agents Chemother 58:3144–3150

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu D, Choi S, Chen B, Doerksen RJ, Clements DJ, Winkler JD, Klein ML, DeGrado WF (2004) Nontoxic membrane-active antimicrobial arylamide oligomers. Angew Chem Int Ed Engl 43:1158–1162

    Article  CAS  PubMed  Google Scholar 

  • Livne L, Kovachi T, Sarig H, Epand RF, Zaknoon F, Epand RM, Mor A (2009) Design and characterization of a broad-spectrum bactericidal acyl-lysyl oligomer. Chem Biol 16:1250–1258

    Article  CAS  PubMed  Google Scholar 

  • Livne L, Epand RF, Papahadjopoulos-Sternberg B, Epand RM, Mor A (2010) OAK-based cochleates as a novel approach to overcome multidrug resistance in bacteria. FASEB J 24:5092–5101

    Article  CAS  PubMed  Google Scholar 

  • Makobongo MO, Gancz H, Carpenter BM, McDaniel DP, Merrell DS (2012) The oligo-acyl lysyl antimicrobial peptide C(1)(2)K-2beta(1)(2) exhibits a dual mechanism of action and demonstrates strong in vivo efficacy against Helicobacter pylori. Antimicrob Agents Chemother 56:378–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mannoor MS, Zhang S, Link AJ, McAlpine MC (2010) Electrical detection of pathogenic bacteria via immobilized antimicrobial peptides. Proc Natl Acad Sci USA 107:19207–19212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marjieh I, Meir O, Zaknoon F, Mor A (2015) Improved bacterial detection using immobilized acyl-lysyl oligomers. Appl Environ Microbiol 81:74–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marr AK, Gooderham WJ, Hancock RE (2006) Antibacterial peptides for therapeutic use: obstacles and realistic outlook. Curr Opin Pharmacol 6:468–472

    Article  CAS  PubMed  Google Scholar 

  • McCallum N, Berger-Bächi B, Senn MM (2010) Regulation of antibiotic resistance in Staphylococcus aureus. Int J Med Microbiol 300:118–129

    Article  CAS  PubMed  Google Scholar 

  • Mensa B, Kim YH, Choi S, Scott R, Caputo GA, DeGrado WF (2011) Antibacterial mechanism of action of arylamide foldamers. Antimicrob Agents Chemother 55:5043–5053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nielsen A, Mansson M, Bojer MS, Gram L, Larsen TO, Novick RP, Frees D, Frøkiær H, Ingmer H (2014) Solonamide B inhibits quorum sensing and reduces staphylococcus aureus mediated killing of human neutrophils. PLoS One 9

    Google Scholar 

  • Padan E, Bibi E, Ito M, Krulwich TA (2005) Alkaline pH homeostasis in bacteria: new insights. Biochim Biophys Acta 1717:67–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paul M, Carmeli Y, Durante-Mangoni E, Mouton JW, Tacconelli E, Theuretzbacher U, Mussini C, Leibovici L (2014) Combination therapy for carbapenem-resistant Gram-negative bacteria. J Antimicrob Chemother 69:2305–2309

    Article  CAS  PubMed  Google Scholar 

  • Paulsen IT, Brown MH, Skurray RA (1996) Proton-dependent multidrug efflux systems. Microbiol Rev 60:575–608

    CAS  PubMed  PubMed Central  Google Scholar 

  • Poole K (2005) Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 56:20–51

    Article  CAS  PubMed  Google Scholar 

  • Poole K (2012) Bacterial stress responses as determinants of antimicrobial resistance. J Antimicrob Chemother 67:2069–2089

    Article  CAS  PubMed  Google Scholar 

  • Radzishevsky IS, Rotem S, Bourdetsky D, Navon-Venezia S, Carmeli Y, Mor A (2007) Improved antimicrobial peptides based on acyl-lysine oligomers. Nat Biotechnol 25:657–659

    Article  CAS  PubMed  Google Scholar 

  • Radzishevsky IS, Kovachi T, Porat Y, Ziserman L, Zaknoon F, Danino D, Mor A (2008) Structure-activity relationships of antibacterial acyl-lysine oligomers. Chem Biol 15:354–362

    Article  CAS  PubMed  Google Scholar 

  • Ratledge C, Wilkinson SG(1988) Microbial lipids. Academic Press, London

    Google Scholar 

  • Reisinger P, Seidel H, Tschesche H, Hammes WP (1980) The effect of nisin on murein synthesis. Arch Microbiol 127:187–193

    Article  CAS  PubMed  Google Scholar 

  • Rompre A, Servais P, Baudart J, de-Roubin MR, Laurent P (2002) Detection and enumeration of coliforms in drinking water: current methods and emerging approaches. J Microbiol Methods 49:31–54

    Article  PubMed  Google Scholar 

  • Rotem S, Mor A (2009) Antimicrobial peptide mimics for improved therapeutic properties. Biochim Biophys Acta 1788:1582–1592

    Article  CAS  PubMed  Google Scholar 

  • Rotem S, Radzishevsky IS, Bourdetsky D, Navon-Venezia S, Carmeli Y, Mor A (2008a) Analogous oligo-acyl-lysines with distinct antibacterial mechanisms. FASEB J 22:2652–2661

    Google Scholar 

  • Rotem S, Radzishevsky IS, Bourdetsky D, Navon-Venezia S, Carmeli Y, Mor A (2008b) Analogous oligo-acyl-lysines with distinct antibacterial mechanisms. FASEB J 22:2652–2661

    Article  CAS  PubMed  Google Scholar 

  • Rotem S, Raz N, Kashi Y, Mor A (2010) Bacterial capture by peptide-mimetic oligoacyllysine surfaces. Appl Environ Microbiol 76:3301–3307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruhr E, Sahl HG (1985) Mode of action of the peptide antibiotic nisin and influence on the membrane potential of whole cells and on cytoplasmic and artificial membrane vesicles. Antimicrob Agents Chemother 27:841–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakoulas G, Okumura CY, Thienphrapa W, Olson J, Nonejuie P, Dam Q, Dhand A, Pogliano J, Yeaman MR, Hensler ME, Bayer AS, Nizet V (2014) Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus. J Mol Med 92:139–149 (Berlin, Germany)

    Google Scholar 

  • Sarig H, Rotem S, Ziserman L, Danino D, Mor A (2008) Impact of self-assembly properties on antibacterial activity of short acyl-lysine oligomers. Antimicrob Agents Chemother 52:4308–4314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarig H, Livne L, Held-Kuznetsov V, Zaknoon F, Ivankin A, Gidalevitz D, Mor A (2010) A miniature mimic of host defense peptides with systemic antibacterial efficacy. FASEB J 24:1904–1913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarig H, Ohana D, Epand R, Mor A, Epand R (2011) Functional studies of cochleate assemblies of an oligo-acyl-lysyl with lipid mixtures for combating bacterial multidrug resistance. FASEB J 25:3336–3343

    Article  CAS  PubMed  Google Scholar 

  • Sass V, Schneider T, Wilmes M, Korner C, Tossi A, Novikova N, Shamova O, Sahl HG (2010) Human beta-defensin 3 inhibits cell wall biosynthesis in Staphylococci. Infect Immun 78:2793–2800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sawyer JG, Martin NL, Hancock RE (1988) Interaction of macrophage cationic proteins with the outer membrane of Pseudomonas aeruginosa. Infect Immun 56:693–698

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schaberle TF, Hack IM (2014) Overcoming the current deadlock in antibiotic research. Trends Microbiol 22:165–167

    Article  PubMed  Google Scholar 

  • Schuerholz T, Brandenburg K, Marx G (2012) Antimicrobial peptides and their potential application in inflammation and sepsis. Crit Care 16:207

    Article  PubMed  PubMed Central  Google Scholar 

  • Shprung T, Peleg A, Rosenfeld Y, Trieu-Cuot P, Shai Y (2012) Effect of PhoP-PhoQ activation by broad repertoire of antimicrobial peptides on bacterial resistance. J Biol Chem 287:4544–4551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silver LL (2011) Challenges of antibacterial discovery. Clin Microbiol Rev 24:71–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silverman JA, Perlmutter NG, Shapiro HM (2003) Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother 47:2538–2544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strahl H, Hamoen W (2010) Membrane potential is important for bacterial cell division. Proc Natl Acad Sci USA 107:12281–12286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sully EK, Malachowa N, Elmore BO, Alexander SM, Femling JK, Gray BM, DeLeo FR, Otto M, Cheung AL, Edwards BS, Sklar LA, Horswill AR, Hall PR, Gresham HD (2014) Selective chemical inhibition of agr quorum sensing in staphylococcus aureus promotes host defense with minimal impact on resistance, PLoS Pathogens 10

    Google Scholar 

  • Vaara M, Fox J, Loidl G, Siikanen O, Apajalahti J, Hansen F, Frimodt-Møller N, Nagai J, Takano M, Vaara T (2008) Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents. Antimicrob Agents Chemother 52:3229–3236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Westerhoff HV, Juretic D, Hendler RW, Zasloff M (1989) Magainins and the disruption of membrane-linked free-energy transduction. Proc Natl Acad Sci USA 86:6597–6601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilke MS, Hills TL, Zhang HZ, Chambers HF, Strynadka NC (2004) Crystal structures of the Apo and penicillin-acylated forms of the BlaR1 beta-lactam sensor of Staphylococcus aureus. J Biol Chem 279:47278–47287

    Article  CAS  PubMed  Google Scholar 

  • Yang SJ, Bayer AS, Mishra NN, Meehl M, Ledala N, Yeaman MR, Xiong YQ, Cheung AL (2012) The Staphylococcus aureus two-component regulatory system, GraRS, senses and confers resistance to selected cationic antimicrobial peptides. Infect Immun 80:74–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Zaknoon F, Wein S, Krugliak M, Meir O, Rotem S, Ginsburg H, Vial H, Mor A (2011) Antiplasmodial properties of acyl-lysyl oligomers in culture and animal models of malaria. Antimicrob Agents Chemother 55:3803–3811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415:389–395

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Dhillon P, Yan H, Farmer S, Hancock RE (2000) Interactions of bacterial cationic peptide antibiotics with outer and cytoplasmic membranes of Pseudomonas aeruginosa. Antimicrob Agents Chemother 44:3317–3321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the Israel Science Foundation (grant 909/12).

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  1. Department of Biotechnology & Food Engineering, Technion-Israel Institute of Technology, 32000, Haifa, Israel

    Amram Mor

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Correspondence to Amram Mor .

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  1. Health Sciences Centre, McMaster University, Hamilton, Ontario, Canada

    Richard M. Epand

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Mor, A. (2016). Engineered OAKs Against Antibiotic Resistance and for Bacterial Detection. In: Epand, R. (eds) Host Defense Peptides and Their Potential as Therapeutic Agents. Springer, Cham. https://doi.org/10.1007/978-3-319-32949-9_8

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