Modified peptides as potential new antibiotics versus multiresistent problem strains

• Applicant: Professor Dr. Nisar Peter Malek, since 6/2019
• Subject Area: Gastroenterology
• Term: from 2017 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 390523201

Antimicrobial peptides are endogenous-, small-, usually cationic peptide antibiotics which represent an essential part of innate immune defense. Different of these peptides have a broad range of antimicrobial but also antifungal and antiviral properties. So far we know more then 800 of these host protective molecules. The best characterized group are human defensins which are characterized by disulfid bridges. According to the order and distribution of these bridges they can be divided in alpha and beta defensins. Defensins are produced by all epithelial cells but also different immune cells. One defensin which is expressed everywhere at the surface is human beta defensin 1 (hBD1). Despite its ubiquitous expression the biological function was unclear for a long time time because of only weak antimicrobial properties under normal standard conditions. Our group could show that antimicrobial activity gets unmasked depending on environmental conditions. This activation by reduction seems to be a general principle of nature as it also applies to other peptides. However, the reduced form of the peptide is not stable towards proteases and can be cleaved by duodenal mucus. After proteolytic cleavage small fragments occur which also have antimicrobial properties. We isolated a fragment which is ative against Grampositive and Gram negative bacteria such as S. aureus and E. coli. To improve binding to the muces we added a fatty acid to this small fragment. The basic idea of this proposal is a combination of natural occuring palimin acid with the new discovered antimicrobial fragment. Surprisingly this combined peptide (of acid and defensin fragment) does not only maintain its antimicrobial function but it becomes much more active and is able to kill different multiresistent strains. Here we aim to further explore the underlining mechanisms and principles by using different layers of investigations.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Jan Wehkamp, until 6/2019