2017/26/E/ST5/00364

2018-2023

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The aim of the project is to fully understand the relationship between antimicrobial peptide-metal coordination, structure, stability, and mode of action. The inspiration for this project comes from the dramatic increase of antimicrobial resistance – the resistance of a microorganism to an antimicrobial drug that was originally effective for treatment. Resistant bacteria and fungi are able to withstand the attack of antibiotics and antifungals, making standard treatments ineffective. Novel, effective treatments and ways to specifically deliver them to drug resistant microbes are being actively sought. Because of the general lack of resistance towards antimicrobial peptides (AMPs), they are being relied on as 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 removal of essential metal ions.

Biologically indispensable metal ions, such as Zn(II) and Cu(II), which are the key players of this project, are substantial for the survival of microbes, being crucial for metalloproteins, such as metalloenzymes, storage proteins and transcription factors. Their effective acquisition is often considered as a virulence factor. For some AMPs, metals act as activity boosters, affecting the AMP charge and/or structure. Taken together, metal ions 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 (removal of metal ions, nutritional immunity) or (ii) AMPs need the given metal ion to boost their antimicrobial activity.

To the best of our knowledge, up to date, although AMP have been intensively studied for more than a decade, no data have been reported to demonstrate a clear relationship between the metal binding ability, structure of an AMP and its mode of action, the degree of activity, or the host range.

In the scope of our project, 38 antimicrobial peptides have been chosen for the initial step of studies. The newly formed team will first focus on the thermodynamics, structure and coordination chemistry of the studied complexes – these studies will be the most fundamental pillar of the proposed project. Impact of the presence of biological membranes will also be taken into account. The comparison of these data to the outcome of biological growth studies on several bacterial and fungal strains will allow us to draw conclusions about the relationship between the metal-antimicrobial peptide complex structure, stability, mode of action and efficacy. In the second step of the project, the most efficient complexes will serve as templates for a rational design of novel, more potent AMP-based therapeutics. Further improvement will be reached through the modification of the most promising AMP complexes using (i) chimeric compounds comprising AMPs bound to conventional antibiotics or antifungal drugs or (ii) specifically targeted antimicrobial peptides, in which the AMP will be covalently linked to a targeting peptide.

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