Abstract
The spread of antibiotic-resistant human pathogens and the declining number of novel antibiotics in the development pipeline is a global challenge that has fueled the demand for alternative options. The search for novel drug candidates has expanded to include not only antibiotics but also adjuvants capable of restoring antibiotic susceptibility in multidrug-resistant (MDR) pathogens. Insect-derived antimicrobial peptides (AMPs) can potentially fulfil both of these functions. We tested two coleoptericins and one coleoptericin-like peptides from the invasive harlequin ladybird Harmonia axyridis against a panel of human pathogens. The AMPs displayed little or no activity when tested alone but were active even against clinical MDR isolates of the Gram-negative ESKAPE strains when tested in combination with polymyxin derivatives, such as the reserve antibiotic colistin, at levels below the minimal inhibitory concentration. Assuming intracellular targets of the AMPs, our data indicate that colistin potentiates the activity of the AMPs. All three AMPs achieved good in vitro therapeutic indices and high intrahepatic stability but low plasma stability, suggesting they could be developed as adjuvants for topical delivery or administration by inhalation for anti-infective therapy to reduce the necessary dose of colistin (and thus its side effects) or to prevent development of colistin resistance in MDR pathogens.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Access to Medicine Foundation (2018) Antimicrobial resistance benchmark 2018: first independent assessment of pharmaceutical company action on AMR
Balouiri M, Sadiki M, Ibnsouda SK (2016) Methods for in vitro evaluating antimicrobial activity: A review. J Pharm Anal 6:71–79. https://doi.org/10.1016/j.jpha.2015.11.005
Beckert A, Wiesner J, Baumann A, Poppel AK, Vogel H, Vilcinskas A (2015) Two c-type lysozymes boost the innate immune system of the invasive ladybird Harmonia axyridis. Dev Comp Immunol 49:303–312. https://doi.org/10.1016/j.dci.2014.11.020
Bolouri Moghaddam MR, Tonk M, Schreiber C, Salzig D, Czermak P, Vilcinskas A, Rahnamaeian M (2016) The potential of the Galleria mellonella innate immune system is maximized by the co-presentation of diverse antimicrobial peptides. Biol Chem 397:939–945. https://doi.org/10.1515/hsz-2016-0157
Brunetti J et al (2016) In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate. Sci Rep 6:26077. https://doi.org/10.1038/srep26077
Casteels P, Tempst P (1994) Apidaecin-type peptide antibiotics function through a non-poreforming mechanism involving stereospecificity. Biochem Biophys Res Commun 199:339–345. https://doi.org/10.1006/bbrc.1994.1234
Chu HL, Yu HY, Yip BS, Chih YH, Liang CW, Cheng HT, Cheng JW (2013) Boosting salt resistance of short antimicrobial peptides. Antimicrob Agents Chemother 57:4050–4052. https://doi.org/10.1128/aac.00252-13
Chung TDY, Terry DB, Smith LH (2015) In vitro and in vivo assessment of ADME and PK properties during lead selection and lead optimization – guidelines, benchmarks and rules of thumb. In: Sittampalam GS et al (eds) Assay guidance manual. Eli Lilly & Company and the National Center for Advancing Translational Sciences, Bethesda (MD), pp 1285–1287
Delaney D, Butter J (2018) Tracking progress to address antimicrobial resistance. AMR Industry Alliance,
Diao L, Meibohm B (2013) Pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of therapeutic peptides. Clin Pharmacokinet 52:855–868. https://doi.org/10.1007/s40262-013-0079-0
Dixon RA, Chopra I (1986) Polymyxin B and polymyxin B nonapeptide alter cytoplasmic membrane permeability in Escherichia coli. J Antimicrob Chemother 18:557–563. https://doi.org/10.1093/jac/18.5.557
Falagas ME, Kasiakou SK, Saravolatz LD (2005) Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 40:1333–1341. https://doi.org/10.1086/429323
Gegner T, Schmidtberg H, Vogel H, Vilcinskas A (2018) Population-specific expression of antimicrobial peptides conferring pathogen resistance in the invasive ladybird Harmonia axyridis. Sci Rep 8:3600. https://doi.org/10.1038/s41598-018-21781-4
Houtmann S, Schombert B, Sanson C, Partiseti M, Bohme GA (2017) Automated Patch-Clamp Methods for the hERG Cardiac Potassium Channel. Methods Mol Biol 1641:187–199. https://doi.org/10.1007/978-1-4939-7172-5_10
Huang J et al (2011) Inhibitory effects and mechanisms of physiological conditions on the activity of enantiomeric forms of an alpha-helical antibacterial peptide against bacteria. Peptides 32:1488–1495. https://doi.org/10.1016/j.peptides.2011.05.023
Jayamani E et al (2015) Insect-derived cecropins display activity against Acinetobacter baumannii in a whole-animal high-throughput Caenorhabditis elegans model. Antimicrob Agents Chemother 59:1728–1737. https://doi.org/10.1128/aac.04198-14
Kang S-J, Park SJ, Mishig-Ochir T, Lee B-J (2014) Antimicrobial peptides: therapeutic potentials. Expert Rev Anti Infect Ther 12:1477–1486. https://doi.org/10.1586/14787210.2014.976613
Kelesidis T, Falagas ME (2015) The safety of polymyxin antibiotics. Expert Opin Drug Saf 14:1687–1701. https://doi.org/10.1517/14740338.2015.1088520
Knappe D, Henklein P, Hoffmann R, Hilpert K (2010) Easy strategy to protect antimicrobial peptides from fast degradation in serum. Antimicrob Agents Chemother 54:4003–4005. https://doi.org/10.1128/aac.00300-10
Koch RL, Costamagna AC (2017) Reaping benefits from an invasive species: role of Harmonia axyridis in natural biological control of Aphis glycines in North America. BioControl 62:331–340. https://doi.org/10.1007/s10526-016-9749-9
Krizsan A, Prahl C, Goldbach T, Knappe D, Hoffmann R (2015) Short proline-rich antimicrobial peptides inhibit either the bacterial 70S ribosome or the assembly of its large 50S subunit. ChemBioChem 16:2304–2308. https://doi.org/10.1002/cbic.201500375
Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132
Lam SJ et al (2016) Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers. Nat Microbiol 1:16162. https://doi.org/10.1038/nmicrobiol.2016.162
Laverty G, Gilmore B (2014) Cationic antimicrobial peptide cytotoxicity. SOJ Microbiol Infect Dis 2:1–8. https://doi.org/10.15226/sojmid.2013.00112
Li H, Sun S-r, Yap JQ, Chen J-h, Qian Q (2016) 0.9% saline is neither normal nor physiological. J Zhejiang Univ Sci B 17:181–187. https://doi.org/10.1631/jzus.B1500201
Li Z et al (2017) Antibacterial and immunomodulatory activities of insect defensins-DLP2 and DLP4 against multidrug-resistant Staphylococcus aureus. Sci Rep 7:12124. https://doi.org/10.1038/s41598-017-10839-4
Login FH et al (2011) Antimicrobial peptides keep insect endosymbionts under control. Science 334:362–365. https://doi.org/10.1126/science.1209728
Maisetta G et al (2008) Evaluation of the inhibitory effects of human serum components on bactericidal activity of human beta defensin 3. Peptides 29:1–6. https://doi.org/10.1016/j.peptides.2007.10.013
Masson F, Zaidman-Remy A, Heddi A (2016) Antimicrobial peptides and cell processes tracking endosymbiont dynamics. Philos Trans R Soc Lond B Biol Sci 371:371. https://doi.org/10.1098/rstb.2015.0298
Mylonakis E, Podsiadlowski L, Muhammed M, Vilcinskas A (2016) Diversity, evolution and medical applications of insect antimicrobial peptides. Philos Trans R Soc Lond, Ser B: Biol Sci 371:20150290. https://doi.org/10.1098/rstb.2015.0290
O’Neill J (2016) Tackling drug-resistant infections globally: final report and recommendations
Papadopoulos JS, Agarwala R (2007) COBALT: constraint-based alignment tool for multiple protein sequences. Bioinformatics 23:1073–1079. https://doi.org/10.1093/bioinformatics/btm076
Pini A et al (2005) Antimicrobial activity of novel dendrimeric peptides obtained by phage display selection and rational modification. Antimicrob Agents Chemother 49:2665–2672. https://doi.org/10.1128/aac.49.7.2665-2672.2005
Poppel AK, Vogel H, Wiesner J, Vilcinskas A (2015) Antimicrobial peptides expressed in medicinal maggots of the blow fly Lucilia sericata show combinatorial activity against bacteria. Antimicrob Agents Chemother 59:2508–2514. https://doi.org/10.1128/aac.05180-14
Poulin P, Kenny JR, Hop CE, Haddad S (2012) In vitro-in vivo extrapolation of clearance: modeling hepatic metabolic clearance of highly bound drugs and comparative assessment with existing calculation methods. J Pharm Sci 101:838–851. https://doi.org/10.1002/jps.22792
Rahnamaeian M et al (2015) Insect antimicrobial peptides show potentiating functional interactions against Gram-negative bacteria. Proc Biol Sci 282:282. https://doi.org/10.1098/rspb.2015.0293
Rahnamaeian M, Cytrynska M, Zdybicka-Barabas A, Vilcinskas A (2016) The functional interaction between abaecin and pore-forming peptides indicates a general mechanism of antibacterial potentiation. Peptides 78:17–23. https://doi.org/10.1016/j.peptides.2016.01.016
Rajamuthiah R et al (2015) A Defensin from the Model Beetle Tribolium castaneum Acts Synergistically with Telavancin and Daptomycin against Multidrug Resistant Staphylococcus aureus. PLoS One 10:e0128576. https://doi.org/10.1371/journal.pone.0128576
Rao A, Chopra S, Ram G, Gupta A, Ranganathan A (2005) Application of the “codon-shuffling” method. Synthesis and selection of de novo proteins as antibacterials. J Biol Chem 280:23605–23614. https://doi.org/10.1074/jbc.M503056200
Rohrich CR et al (2012) Harmonine, a defence compound from the harlequin ladybird, inhibits mycobacterial growth and demonstrates multi-stage antimalarial activity. Biol Lett 8:308–311. https://doi.org/10.1098/rsbl.2011.0760
Roy HE et al (2016) The harlequin ladybird, Harmonia axyridis: global perspectives on invasion history and ecology. Biol Invasions 18:997–1044. https://doi.org/10.1007/s10530-016-1077-6
Schmidtberg H, Röhrich C, Vogel H, Vilcinskas A (2013) A switch from constitutive chemical defence to inducible innate immune responses in the invasive ladybird <em>Harmonia axyridis biol Lett 9. https://doi.org/10.1098/rsbl.2013.0006
Stern S, Chorzelski S, Franken L, Völler S, Rentmeister H, Grosch B (2017) Breaking through the wall: a call for concerted action on antibiotics research and development. Global Union for Antibiotics Research and Development (GUARD) Initiative, Berlin
Tangden T, Giske CG (2015) Global dissemination of extensively drug-resistant carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control. J Intern Med 277:501–512. https://doi.org/10.1111/joim.12342
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
Tonk M, Vilcinskas A (2017) The medical potential of antimicrobial peptides from insects. Curr Top Med Chem 17:554–575
Vaara M, Viljanen P, Vaara T, Mäkelä PH (1984) An outer membrane-disorganizing peptide PMBN sensitizes E. coli strains to serum bactericidal action. J Immunol 132:2582–2589
Verheggen FJ, Vogel H, Vilcinskas A (2017) Behavioral and Immunological Features Promoting the Invasive Performance of the Harlequin Ladybird Harmonia axyridis. Front Ecol Evol 5. https://doi.org/10.3389/fevo.2017.00156
Vilcinskas A, Mukherjee K, Vogel H (2013) Expansion of the antimicrobial peptide repertoire in the invasive ladybird Harmonia axyridis. Proc Biol Sci 280:20122113. https://doi.org/10.1098/rspb.2012.2113
Vogel H, Schmidtberg H, Vilcinskas A (2017) Comparative transcriptomics in three ladybird species supports a role for immunity in invasion biology. Dev Comp Immunol 67:452–456. https://doi.org/10.1016/j.dci.2016.09.015
Walser M (1961) Ion association. VI. Interactions between calcium, magnesium, inorganic phosphate, citrate and protein in normal human plasma. J Clin Invest 40:723–730
WHO (2017) Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, including tuberculosis. WHO, Geneva
Zheng Z et al (2017) Synergistic efficacy of Aedes aegypti antimicrobial peptide Cecropin A2 and tetracycline against Pseudomonas aeruginosa. Antimicrob Agents Chemother 61. https://doi.org/10.1128/aac.00686-17
Acknowledgments
We thank Dr. Yvonne Pfeifer for providing the multidrug-resistant clinical isolates from the strain library of the Robert Koch Institute in Wernigerode. We thank Kirsten-Susann Bommersheim, Sibylle Müller-Bertling, and Kirstin Ganske for excellent technical assistance and Dr. Richard M. Twyman for professional editing of the manuscript.
Conflict of Interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Appendix
Appendix
Rights and permissions
Copyright information
© 2018 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Hirsch, R., Wiesner, J., Marker, A., Bauer, A., Hammann, P.E., Vilcinskas, A. (2018). Biological Profiling of Coleoptericins and Coleoptericin-Like Antimicrobial Peptides from the Invasive Harlequin Ladybird Harmonia axyridis . In: Donelli, G. (eds) Advances in Microbiology, Infectious Diseases and Public Health. Advances in Experimental Medicine and Biology(), vol 1214. Springer, Cham. https://doi.org/10.1007/5584_2018_276
Download citation
DOI: https://doi.org/10.1007/5584_2018_276
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-35468-8
Online ISBN: 978-3-030-35469-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)