P6: Antimicrobial and immunodulatory activities of (hidden) host defense peptides

Host defense peptides (HDPs), also referred to as antimicrobial peptides (AMPs), are effectors of innate immunity found in all trees of life that combine various activities, including direct antimicrobial and immunomodulatory properties.

Although evolutionary ancient, HDPs retained antimicrobial efficacy and do not easily select for resistant mutants and thus represent promising alternatives to conventional antibiotics. Because of their cationic amphipathic nature, HDPs are known to disturb bacterial membrane functions and/or modulate innate immune responses, but the mechanisms and specificities of action are yet not fully understood, hampering rational development.

This proposal aims to provide significant insights into the antibiotic and immunomodulatory mechanisms of action (MoA) of selected endogenous and synthetic HDPs by using a comprehensive and multidisciplinary approach in combination with transcriptomics, proteomics, advanced fluorescence microscopy and innovative membrane bilayer analytics as well as extensive pharmacological analyses.

The Schneider group will focus on cryptic HDPs (‘cryptides’) with previously hidden activities, which were recently identified in apolipoproteins (Apo). It is hypothesized that the MoA of cryptides is much more directed, likely involving the interaction with specific bacterial target molecules.

The antimicrobial MoAs of selected Apo cryptides and optimized synthetic variants will be elucidated, and their potential as monotherapeutics as well as combination partners of established antibiotics will be evaluated. The Weindl group will identify and define novel receptors and signalling pathways modulated by small, cationic endogenous and synthetic HDPs to shed light on previously unrecognized effects on host cells and explain underlying mechanisms of known immunomodulatory effects.

This is aimed to fill the significant knowledge gap in the mechanistic details of immunity-related functions to open the door for the design of next-generation HDPs. Collaborations are planned with P3 and P4 (biological activities of macrocycles), P2 (supply of synthetic HDPs), P9 (conjugates) and TP1 (compound library).