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

The phenomenon of antimicrobial resistance is a global major concern and the necessity of new antimicrobial agents represents a scientific challenge that urgently needs to be solved. 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-mer antimicrobial peptide named calcitermin (VAIALKAAHYHTHKE) has been isolated [1]. Calcitermin contains a metal-binding domain with three alternated histidine residues (His9, His11 and His13) and the free terminal amino and carboxyl groups. Based on our preliminary studies, it exhibits an improved microbicidal activity in presence of Zn2+ or Cu2+ ions. Moreover, 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 [2]. These promising results prompted us to focus on calcitermin derivatives where the peptide structure is modified to confer higher proteolytic stability and to study the impact of metal coordination on the antimicrobial efficacy of the peptide, in order to propose and design new therapeutic antimicrobial strategies. C- and/or N- terminal modifications have been introduced to obtain calcitermin derivatives resistant to proteases [3]. The terminal protection, however, can affect calcitermin metal-binding behaviour and therefore further investigations on the metal interaction with the synthesized protected peptides have been performed, in order 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 and EPR. Financial support of the Polish National Science Centre (UMO-2020/37/N/ST4/03165) is gratefully acknowledged. This contribution is based upon work from COST Action CA18202, NECTAR - Network for Equilibria and Chemical Thermodynamics Advanced Research, supported by COST (European Cooperation in Science and Technology). References: [1] M. Cole, Y.-H. Kim, S. Tahk, T. Hong, P. Weis, A. J. Waring, T. Ganz, FEBS Lett. 2001, 504 (), 5-10. [2] D. Bellotti, M. Toniolo, D. Dudek, A. Mikołajczyk, R. Guerrini, A. Matera-Witkiewicz, M. Remelli, M. Rowińska-Żyrek, Dalton Trans. 2019, 48 (), 13740-13752. [3] P. Vlieghe, V. Lisowski, J. Martinez, M. Khrestchatisky, Drug Discov. Today 2010, 15 (), 40-56.