Oddziaływanie przeciwdrobnoustrojowych peptydów z jonami metali : relacja między chemią koordynacyjną, strukturą, termodynamiką a sposobem działania

Increasing bacterial and fungal drug resistance makes novel, effective antimicrobial treatments actively sought. Because of the general lack of resistance towards antimicrobial peptides (AMPs), they are being relied on as a novel class of therapeutics aimed to conquer drug-resistant bacteria and fungi. There are numerous ways in which AMPs might interact with pathogens, such as membrane disruption, production of reactive oxygen species, inhibition of cell wall, nucleic acid and protein synthesis or by the withdrawal of essential metal ions. Biologically indispensable metal ions, such as Zn(II) and Cu(II), which are the key players of this project, have a dual effect on the activity of antimicrobial peptides: (i) AMPs bind them, so that microbes cannot get enough metals essential for their life and virulence (withdrawal of metal ions, nutritional immunity) or (ii) AMPs need the given metal ion as a booster of their antimicrobial activity (metal ions affect the AMP charge and/or structure). In this chapter, we discuss the impact of the coordination of Cu(II) and Zn(II) to several antimicrobial peptides, focusing on the thermodynamics, structure and coordination chemistry. The comparison of these data to the outcome of biological growth studies (determination of minimal inhibitory concentration (MIC) of metalAMP complexes and their derivatives allows to draw conclusions about the relationship between the metal-antimicrobial peptide complex structure, stability mode of action and efficacy. In the nearest future, the most efficient complexes may serve as templates for a rational design of novel, more potent AMP-based therapeutics. Further improvement can be reached through the modification of the most promising AMP complexes using (i) specifically targeted antimicrobial peptides, in which the AMP will be covalently linked to a targeting peptide (Figure 1) or (ii) chimeric compounds comprising AMPs bound to conventional antimicrobials or peptidomimetic modifications (Figure 2).