Abstract
Antimicrobial peptides (AMPs) are amino acid-based bioactive molecules that specifically target microbes. As such, they are a potent class of antibiotics, especially against bacterial infections. Naturally occurring AMPs are usually too long to be considered for therapeutic applications. To solve this, short sequences that mimic the activity of AMPs are designed. However, such endeavors are often accompanied with a reduction in antibacterial activity. To counter this, lipophilic molecules can be attached that function as a lipid anchor and target the short sequence to the bacterial membrane. For a range of short AMPs, this strategy has proven to lead to more active constructs. Although these lipidated short AMPs often work as complex target specific surfactants, more delicate modes of action that do not deviate too much from the nonlipidated counterparts are also known. This is readily observed by the large differences in activities that are detected when alterations in the lipid chain length and chirality of the amino acids residues are implemented. It is not uncommon to see that inactive or poorly active short AMPs can be turned into potent antibacterial agents. Importantly, selectivity of the short lipidated AMPs (lipoAMPs) for the bacterial membrane can be enhanced by alteration of the amino acid chirality. This strategy has led to lipoAMPs with submicromolar activities; in fact, activities that rival that of vancomycin have been observed for several short AMPs. Future research needs to determine (i) the effect of lipidation on the formation of lipid rafts in the bacterial membrane, (ii) if structural complications like branched lipids or chiral substituents on the lipid chain can be used to further increase the activity and selectivity of the conjugates, and (iii) if additional functionalities other than a membrane-anchoring ability can be bestowed on the lipid chain, e.g., redox activity or scavenger for small molecular components that traverse the lipid membrane. The interplay between degree of lipophilicity and the chirality of the amino acids of the AMP also needs further exploration, especially to see if more potent and selective (lipo)AMPs can be obtained that can be applied systemically. It may also be advisable to measure the most potent lipoAMPs in a centralized facility in order to obtain objective and comparable antibacterial activities.
References
Albada HB, Chiriac AI, Wenzel M, Penkova M, Bandow JE, Sahl HG, Metzler-Nolte N (2012a) Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups. Beilstein J Org Chem 8:1753–1764. https://doi.org/10.3762/bjoc.8.200
Albada HB, Prochnow P, Bobersky S, Langklotz S, Schriek P, Bandow JE, Metzler-Nolte N (2012b) Tuning the activity of a short Arg-Trp antimicrobial peptide by lipidation of a C- or N-terminal lysine residue. ACS Med Chem Lett 3:980–984. https://doi.org/10.1021/ml300148v
Albada HB, Prochnow P, Bobersky S, Langklotz S, Bandow JE, Metzler-Nolte N (2013) Short antibacterial peptides with significantly reduced hemolytic activity can be identified by a systematic L-to-D exchange scan of their amino acid residues. ACS Comb Sci 15:585–592. https://doi.org/10.1021/co400072q
Albada HB, Prochnow P, Bobersky S, Schriek P, Bandow JE, Metzler-Nolte N (2014) Highly active antibacterial ferrocenoylated or ruthenocenoylated Arg-Trp peptides can be discovered by an L-to-D substitution scan. Chem Sci 5:4453–4459. https://doi.org/10.1039/c4sc01822b
Arnusch CJ, Albada HB, Van Vaardegem M, Liskamp RMJ, Sahl HG, Shadkchan Y, Osherov N, Shai Y (2012) Trivalent ultrashort lipopeptides are potent pH dependent antifungal agents. J Med Chem 55:1296–1302. https://doi.org/10.1021/jm2014474
Benamara H, Rihouey C, Abbes I, Ben Mlouka MA, Hardouin J, Jouenne T, Alexandre S (2014) Characterization of membrane lipidome changes in Pseudomonas aeruginosa during biofilm growth on glass wool. PLoS One 9(9):e108478. https://doi.org/10.1371/journal.pone.0108478
Blaskovich MAT, Hansford KA, Gong Y, Butler MS, Muldoon C, Huang JX, Ramu S, Silva AB, Cheng M, Kavanagh AM, Ziora Z, Premraj R, Lindahl F, Bradford TA, Lee JC, Karoli T, Pelingon R, Edwards DJ, Amado M, Elliott AG, Phetsang W, Daud NH, Deecke JE, Sidjabat HE, Ramaologa S, Zuegg J, Betley JR, Beevers APG, Smith RAG, Roberts JA, Paterson DL, Cooper MA (2018) Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria. Nat Commun 9:22. https://doi.org/10.1038/s41467-017-02123-w
Boman HG (1995) Peptide antibiotics and their role in innate immunity. Annu Rev Immunol 13:61–92. https://doi.org/10.1146/annurev.iy.13.040195.000425
Brotman Y, Makovitzki A, Shai Y, Chet I, Viterbo A (2009) Synthetic ultrashort cationic lipopeptides induce systemic plant defense response against bacterial and fungal pathogens. Appl Environ Microbiol 75(16):5373–5379. https://doi.org/10.1128/AEM.00724-09
Brunsveld L (2009) Elucidation of the Ras cycle with semi-synthetic proteins. In: Waldmann E, Janning P (eds) Chemical biology: learning through case studies, 1st edn. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 175–187
Cheng JTJ, Hale JD, Elliott M, Hancock REW, Straus SK (2010) The importance of bacterial membrane composition in the structure and function of aurein 2.2 and selected variants. BBA Membr 1808:622–633. https://doi.org/10.1016/j.bbamem.2010.11.025
Chongsiriwatana NP, Miller TM, Wetzler M, Vakulenko S, Karlsson AJ, Palecek SP, Mobashery S, Barron AE (2011) Short alkylated peptoid mimics of antimicrobial lipopeptides. Antimicrob Agents Chemother 55(1):417–420. https://doi.org/10.1128/AAC.01080-10
De Gier M, Albada HB, Josten M, Willems R, Leavis H, Van Mansveld R, Paganelli FL, Dekker B, Lammers JWJ, Sahl HG, Metzler-Nolte N (2016) Synergistic activity of a short lipidated antimicrobial peptide (lipoAMP) and colistin or tobramycin against Pseudomonas aeruginosa from cystic fibrosis patients. Med Chem Commun 7:148–156. https://doi.org/10.1039/c5md00373c
Dunnick JK, O’Leary WM (1970) Correlation of bacterial lipid composition with antibiotic resistance. J Bacteriol 101(3):892–900
Epand RM, Epand RF (2009) Lipid domains in bacterial membranes and the action of antimicrobial agents. BBA Membr 1788:289–294. https://doi.org/10.1016/j.bbamem.2008.08.023
Fauchère JL, Pliska V (1983) Hydrophobic parameters π of amino-acid side chains from the partitioning of N-acetyl-amino acid amides. Eur J Med Chem Chim Ther 18(4):369–375
Goldfine H (1982) Lipids of prokaryotes-structure and distribution. Curr Top Membr Transp 17:1–43. https://doi.org/10.1016/S0070-2161(08)60307-X
Hancock RE, Sahl HG (2006) Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 24(12):1551–1557. https://doi.org/10.1038/nbt1267
Hancock RE, Brown KL, Mookherjee N (2006) Host defence peptides from invertebrates – emerging antimicrobial strategies. Immunobiology 211:315–322. https://doi.org/10.1016/j.imbio.2005.10.017
Haug BE, Stensen W, Stiberg T, Svendsen JS (2004) Bulky nonproteinogenic amino acids permit the design of very small and effective cationic antibacterial peptides. J Med Chem 47(17): 4159–4162. https://doi.org/10.1021/jm049582b
Haug BE, Stensen W, Kalaaij M, Rekdal Ø, Svendsen JS (2008) Synthetic antimicrobial peptidomimetics with therapeutic potential. J Med Chem 51(14):4306–4314. https://doi.org/10.1021/jm701600a
Hu Y, Amin MN, Padhee S, Wang RE, Qiao Q, Bai G, Li Y, Mathew A, Cao C, Cai J (2012) Lipidated peptidomimetics with improved antimicrobial activity. ACS Med Chem Lett 3:683–686. https://doi.org/10.1021/ml3001215
Jaskiewicz M, Neubauer D, Wojciech K (2017) Comparative study on Antistaphylococcal activity of lipopeptides in various culture media. Antibiotics 6:15. https://doi.org/10.3390/antibiotics6030015
Koopmans T, Wood TM, ‘t Hart P, Kleijn LHJ, Hendrickx APA, Willems RJL, Breukink E, Martin NI (2015) Semisynthetic lipopeptides derived from nisin display antibacterial activity and lipid II binding on par with that of the parent compound. J Am Chem Soc 137(29): 9382–9389. https://doi.org/10.1021/jacs.5b04501.
Makovitzki A, Avrahami D, Shai Y (2006) Ultrashort antibacterial and antifungal lipopeptides. Proc Natl Acad Sci USA 103(43):15997–16002. https://doi.org/10.1073/pnas.0606129103
Makovitzki A, Viterbo A, Brotman Y, Chet I, Shai Y (2007) Inhibition of fungal and bacterial plant pathogens in vitro and in planta with ultrashort cationic lipopeptides. Appl Environ Microbiol 73(20):6629–6636. https://doi.org/10.1128/AEM.01334-07
Mangoni ML, Shai Y (2011) Short native antimicrobial peptides and engineered ultrashort lipopeptides: similarities and differences in cell specificities and modes of action. Cell Mol Life Sci 68:2267–2280. https://doi.org/10.1007/s00018-011-0718-2
McKerrow G (2003) Roche prices enfuvirtide (T-20) at %18980 a year – making it the most expensive HIV drug yet. http://i-base.info/htb/10939
Nguyen LT, Haney EF, Vogel HJ (2011) The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol 29(9):464–472. https://doi.org/10.1016/j.tibtech.2011.05.001
Selsted ME, Ouellette AJ (2005) Mammalian defensins in the antimicrobial immune response. Nat Immunol 6:551–557. https://doi.org/10.1038/ni1206
Serrano GN, Zhanel GG, Schweizer F (2009) Antibacterial activity of ultrashort cationic lipo-β-peptides. Antimicrob Agents Chemother 53(5):2215–2217. https://doi.org/10.1128/AAC.01100-08
Shai Y (2002) Mode of action of membrane active antimicrobial peptides. Biopolymers 66:236–248. https://doi.org/10.1002/bip.10260
Shaw N (1974) Lipid composition as a guide to the classification of bacteria. Adv Appl Microbiol 17:63–108
Sohlenkamp C, Geiger O (2016) Bacterial membrane lipids: diversity in structures and pathways. FEMS Microbiol Rev 40:133–159. https://doi.org/10.1093/femsre/fuv008
Strøm MB, Haug EH, Skar ML, Stensen W, Stiberg T, Svendsen JS (2007) The pharmacophore of short cationic antibacterial peptides. J Med Chem 46(9):1567–1570. https://doi.org/10.1021/jm0340039
Svenson J, Brandsdal B-O, Stensen W, Svendsen JS (2007) Albumin binding of short cationic antimicrobial micropeptides and its influence on the in vitro bactericidal effect. J Med Chem 50(14):3334–3339. https://doi.org/10.1021/jm0703542
Teixeira V, Feio MJ, Bastos M (2012) Role of lipids in the interaction of antimicrobial peptides with membranes. Prog Lipid Res 51:149–177. https://doi.org/10.1016/j.plipres.2011.12.005
Vallon-Eberhard A, Makovitzki A, Beauvais A, Latgé JP, Jung S, Shai Y (2008) Efficient clearance of Aspergillus fumigatus in muringe lungs by an ultrashort antimicrobial Lipopeptide, Palmitoyl-Lys-Ala-DAla-Lys. Antimicrob Agents Chemother 52(9):3118–3126. https://doi.org/10.1128/AAC.00526-08
Vance DE, Vance JE (2002) Chapter 1: Functional roles of lipids in membranes by Dowhan W, Bogdanov M. In: Biochemistry of lipids, lipoproteins and membranes. Elsevier, Amsterdam
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. https://doi.org/10.1093/nar/gkv1278
Wenzel M, Chiriac AI, Otto A, Zweytick D, May C, Schumacher C, Gust R, Albada HB, Penkova M, Krämer U, Erdmann R, Metzler-Nolte N, Straus SK, Bremer E, Becher D, Brötz-Österhelt H, Sahl HG, Bandow JE (2014) Small cationic antimicrobial peptides delocalize peripheral membrane proteins. Proc Natl Acad Sci USA 111:E1409–E1418. https://doi.org/10.1073/pnas.1319900111
Wenzel M, Senges CH, Zhang J, Suleman S, Nguyen M, Kumar P, Chiriac AI, Stepanek JJ, Raatschen N, May C, Krämer U, Sahl HG, Straus SK, Bandow JE (2015) Antimicrobial peptides from the aurein family form ion-selective pores in Bacillus subtilis. Chembiochem 16(7):1101–1108. https://doi.org/10.1002/cbic.201500020
Wenzel M, Schriek P, Prochnow P, Albada HB, Metzler-Nolte N, Bandow JE (2016a) Influence of lipidation on the mode of action of a small RW-rich antimicrobial peptide. Biochim Biophys Acta 1858:1004–1011. https://doi.org/10.1016/j.bbamem.2015.11.009
Wenzel M, Prochnow P, Mowbray C, Vuong C, Höxtermann S, Stepanek JJ, Albada HB, Hall J, Metzler-Nolte N, Bandow JE (2016b) Towards profiles of resistance development and toxicity for the small cationic hexapeptide RWRWRW-NH2. Front Cell Dev Biol 4:86. https://doi.org/10.3389/fcell.2016.00086
Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415:389–395. https://doi.org/10.1038/415389a
Acknowledgments
I thank my colleagues from my period in Germany, in alphabetical order: Julia Bandow, Heike Brötz-Österhelt, Nils Metzler-Nolte, Hans-Georg Sahl, and Michaela Wenzel. Furthermore, I thank my current colleagues at the Wageningen University for their fruitful discussions and highly inspirational scientific working environment.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this entry
Cite this entry
Albada, B. (2019). Tuning Activity of Antimicrobial Peptides by Lipidation. In: Goldfine, H. (eds) Health Consequences of Microbial Interactions with Hydrocarbons, Oils, and Lipids. Handbook of Hydrocarbon and Lipid Microbiology . Springer, Cham. https://doi.org/10.1007/978-3-319-72473-7_27-1
Download citation
DOI: https://doi.org/10.1007/978-3-319-72473-7_27-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-72473-7
Online ISBN: 978-3-319-72473-7
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences