Biological Profiling of Coleoptericins and Coleoptericin-Like Antimicrobial Peptides from the Invasive Harlequin Ladybird Harmonia axyridis
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.
KeywordsAnti-infectives Antimicrobial peptides Biological profiling Coleoptericin Harmonia axyridis
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.
- Access to Medicine Foundation (2018) Antimicrobial resistance benchmark 2018: first independent assessment of pharmaceutical company action on AMRGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 1285–1287Google Scholar
- Delaney D, Butter J (2018) Tracking progress to address antimicrobial resistance. AMR Industry Alliance,Google Scholar
- O’Neill J (2016) Tackling drug-resistant infections globally: final report and recommendationsGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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, BerlinGoogle Scholar
- 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
- WHO (2017) Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, including tuberculosis. WHO, GenevaGoogle Scholar
- 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