Multicellular organisms fend off topological fungal and bacterial infections by peptide-derived broad-spectrum antibiotics termed antimicrobial peptides (AMPs). AMPs often directly compromise the integrity of microbial cell membranes - the ‘Achilles heel’ of a bacterial cell - thereby evading efficient pathways of resistance development in bacterial cells. The principles underlying the AMP process in killing are unlike to traditional antibiotics and consequently, AMPs can form the basis for next generation of antibiotics. Currently there are ~20 AMP-derived molecules in clinical trials of Phase I–III among which is OEP-145, a homolog of LL-37, and peptide we intensively study. To understand the antibiotic mechanism of human AMPs we study Dermcidin, LL-37 and SMAP-29 with respect to their putative killing mechanism using X-ray crystallography, electron microscopy, various biochemical methods and medical microbiology approaches (biofilm, activity studies). Supported by molecular dynamic simulations and membrane physiology we gained deep insights into the fascinating mechanism of function (see Fig. 2). Several AMPs (including DCD and LL-37) are active against multi-resistant bacterial strains, hence, rationally enhanced and stabilized variants can have the potential to treat bacterial infections that are no longer susceptible to traditional antibiotic agents. Within 5-10 years we anticipate these results to form a solid basis for the structure-based, rational design of new AMP-derived antibiotic agents.
Despite the success in AMPs defending bacterial infections and the identification of a large number of AMPs used in pharmacological studies, their mechanistic and structural basis remains largely speculative. There are currently many open questions in the field of antimicrobial peptides regarding their targeting and killing mechanisms which we address in our current research as the primary aim. Based on the thorough understanding of these mechanisms we can contribute to the rational development of AMPs as antibiotics structure-based peptide engineering. Using mixtures of LL-37 and truncated variants in the presence of auxiliary molecules we are able to significantly shift their MICs towards the lower nanomolar range. We have recently solved a large number of AMP structures (OEP-145, SMAP, magainin, LL-37, PSM1 and PSM3 and DCD) crystallized in the presence of detergents to understand their structural transition induced by these membrane mimicking molecules. Based on this exquisite structural information and in combination with chemical biology we are aiming to improve the MIC activity of AMPs towards bacteria to further increase their efficiency (the minimal inhibitory concentrations, MIC).
|Kort titel||Antimicrobial peptides|