Calcitermin and its peptide derivatives as promising antimicrobial agents with metal chelating ability

Thanks to the broad spectrum of activity and scarce attitude to induce antimicrobial resistance, antimicrobial peptides (AMPs) represent a rational chance to overcome the current drug-resistance crisis. Among several uncharacterized molecules that contribute to the overall antimicrobial activity of human nasal fluid, a 15-residue antimicrobial peptide named calcitermin (VAIALKAAHYHTHKE) has been identified [1]. Calcitermin contains a metal-binding domain with three alternated histidine residues (His9, His11 and His13) and the free terminal amino and carboxyl groups (Figure 1). It also exhibits an improved microbicidal activity when Zn2+ or Cu2+ ions are present in the culture medium [2]. Additionally, calcitermin His-to-Ala mutants – where each histidine residue is replaced with one alanine – have different metal coordination modes, resulting in significant changes of the antimicrobial properties. These results prompted us to focus on calcitermin derivatives where the peptide structure is modified to confer higher proteolytic stability but maintaining the metal chelating ability. Therefore, C- and/or N- terminal modifications have been introduced to possibly obtain calcitermin derivatives resistant to proteases [3]. Changes in the peptide backbone can affect the metal-binding behaviour and therefore further investigations on Zn2+ and Cu2+ interaction with calcitermin analougues are required to connect the antimicrobial activity with the complex-formation ability. The characterization of metal complexes has been performed by means of several techniques, including potentiometry, high-resolution mass spectrometry, UV-Vis, circular dichroism, NMR and EPR. The obtained results will allow us to propose and design new therapeutic antimicrobial strategies based on calcitermin derivatives and their metal complexes. Financial support of the Polish National Science Centre (UMO-2020/37/N/ST4/03165) is gratefully acknowledged. References [1] Cole, A. M., Kim, Y.-H., Tahk, S., Hong, T., Weis, P., Waring, A. J., Ganz, T. Calcitermin, a novel antimicrobial peptide isolated from human airway secretions. FEBS Lett., 504 (2001) 5-10. [2] Bellotti, D., Toniolo, M., Dudek, D., Mikołajczyk, A., Guerrini, R., Matera-Witkiewicz, A., Remelli M., Rowińska-Żyrek, M., Dalton Trans., 48 (2019) 13740-13752. [3] Vlieghe, P., Lisowski V., Martinez J., Khrestchatisky M. Synthetic therapeutic peptides: science and market. Drug Discov. Today, 15 (2010) 40-56.