The Synergy Between Zinc and Antimicrobial Peptides: An Insight into Unique Bioinorganic Interactions

Abstract

Antimicrobial peptides (AMPs) are essential components of innate immunity across all species. AMPs have become the focus of attention in recent years as scientists are addressing antibiotic resistance, a public health crisis that has reached epidemic proportions. This family of peptides are a promising alternative to current antibiotics due to their broad-spectrum antimicrobial activity and tendency to avoid resistance development. A subfamily of AMPs interact with metal ions to potentiate their antimicrobial effectiveness, as such they have been termed metalloAMPs. In this work, we review the scientific literature of metalloAMPs that enhance their antimicrobial efficacy when combined with the essential metal ion, zinc (II). Beyond the role played by Zn(II) as a cofactor in different systems, it is well-known that this metal ion plays an important role in innate immunity. Here, we classify the different types of synergistic interactions between AMPs and Zn(II) into three distinct classes. By better understanding how each class of metalloAMPs uses Zn(II) to potentiate their activity, researchers can begin to exploit these interactions in the development of new antimicrobial agents and accelerate their use as therapeutics.

Capping motifs in antimicrobial peptides and their relevance for improved biological activities

“…In class III, cations may indirectly influence the activity of an AMP, and the existence of an ion-AMP complex is not a requirement. In this scenario, the cation enhances the activity of an AMP by inhibiting the microbe's responses (Donaghy et al, 2023).…”

“…One such examples is ixosine, a peptide isolated from the tick Ixodes sinensis, which exhibits a similar effect on the lipid membranes of bacteria. The mechanism also appears to be class I, according to the classification by Donaghy et al (2023), through a strategy employed by the tick in using Cu 2+ ions as part of the activation of its immune defense against bacterial infections. In the case of ixosine (Gly-Leu-His-Lys-Val-Met-Arg-Glu-Val-Leu-Gly-Tyr-Glu-Arg-Asn-Ser-Tyr-Lys-Lys-Phe-Phe-Leu-Arg), the first three amino acids (Gly-Leu-His) are the motif responsible and that can coordinate to Cu 2+ and Ni 2+ .…”

“…These cationic α-helix AMPs usually as stable or unstable pore formers. The unstable pores can generate a reorganization of the membrane surface and consequently reorient proteins and receptors, resulting in a change in the transmembrane potential, causing an imbalance and cell death (Łoboda et al, 2018;Donaghy et al, 2023). However, just as helices can be formed and incorporated within the membrane to form pores, so can several different types of amphipathic structures be formed, not necessarily imposed by a strict primary or secondary structural organization (Tossi et al, 2000).…”

“…However, just as helices can be formed and incorporated within the membrane to form pores, so can several different types of amphipathic structures be formed, not necessarily imposed by a strict primary or secondary structural organization (Tossi et al, 2000). As well as helical amphipathic, resulting in part from punctual interactions of the residues within a given sequence, other environmental factors such as pH conditions, ionic strength, and the presence of divalent cations are responsible for AMP activity effectiveness (Donaghy et al, 2023).…”

Semenogelins Armed in Zn(II) and Cu(II): May Bioinorganic Chemistry Help Nature to Cope with Enterococcus faecalis?

“…Interestingly, it is also proposed that the antimicrobial activity of semenogelin fragments is Zn 2+ -dependent–the removal of Zn 2+ ions from the semen plasma causes almost a complete inhibition of semenogelins’ antimicrobial properties, while Zn 2+ readdition restores their antibacterial activity . In contrast, Edstrom et al did not clearly confirm the antimicrobial effect of SgI and SgII as it was proposed by Bourgeon et al Taken together, this urged us to elucidate the semenogelin Zn 2+ - and Cu 2+ -binding modes and to understand the relationship between the complexes’ coordination, structure, stability, and mode of action, keeping in mind that in general, metal ions may have a dual effect on the activity of antimicrobial peptides (AMPs): (i) AMPs bind them, so that microbes cannot get enough metals essential for their life and virulence (removal of metal ions, nutritional immunity) or (ii) AMPs need the given metal ion to boost their antimicrobial activity via affecting their charge and/or structure. − …”