Beyond the thermodynamics of metal-peptide complexes: new perspectives for antimicrobial agents

The importance of antibiotics to fight infectious diseases is undoubtedly well recognised worldwide. However, the antimicrobial resistance of many microorganisms has forced to reevaluate their application. Antimicrobial peptides are promising alternatives to classical antibiotics. Their bioactivity can arise from different mechanisms, one of which is known as nutritional immunity and has metal micronutrients and metal-binding biomolecules as its main players. The human antimicrobial peptide calcitermin is an example. It has been previously studied by our research group aiming to evaluate its metal chelating ability and bioactivity against various pathogens in vitro.1 A systematic study was further undertaken on calcitermin derivatives. Chemical modifications have been introduced in the native sequence to verify the impact of divalent Cu(II) and Zn(II) ions on the stability, coordination and antimicrobial activity of the formed complexes.2,3 A deep investigation of complex formation equilibria and coordination chemistry of the formed species has been obtained by means of potentiometric titrations, mass spectrometry, UV-Vis spectrophotometry, circular dichroism and electronic paramagnetic resonance. Antimicrobial assays provided information on the bioactivity of the compounds against a wide panel of microorganisms and highlighted the crucial role of metal ions. Given the obtained results, the characterization of the thermodynamic properties in solution of metal-peptide complexes represents a stepping-stone for the development of new metal-based antimicrobial agents. Financial support of the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.1 – NextGenerationEU (PRIN PNRR 2022 - P2022EMY52) is gratefully acknowledged.