J4-70164 Novel engineered protein nanoparticles to combat drug-resistant infections: oligolysins
Through iterative development and computational optimization of phage-encoded hydrolases, this project aims to discover innovative enzymes with strong antibacterial activity.
As antimicrobial resistance (AMR) continues to pose a serious global health threat—driving high morbidity, mortality, prolonged treatments, and increased healthcare costs—the need for alternative antimicrobial strategies is urgent, especially against multidrug-resistant, biofilm-forming pathogens.The project focuses on alternative approaches against key pathogens such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis by exploiting the potential of two classes of hydrolase enzymes encoded by bacteriophages (phages), endolysins and polysaccharide depolymerases. Endolysins are peptidoglycan-degrading enzymes that cause rapid bacterial cell death and act independently of bacterial metabolism, including in biofilms. Depolymerases degrade extracellular polysaccharides such as capsules and lipopolysaccharides, disrupting protective layers and biofilm matrices in Gram-negative bacteria. Within the project, we will generate recombinant wild-type endolysins and depolymerases, their functional domains, and various fusion proteins, and incorporate a protein scaffold approach. By creating several generations of proteins with increasing complexity, we will optimize proteins in terms of biochemical properties and antibacterial activity, cytotoxicity and stability.
COBIK, the leading project partner, maintains an extensive collection of clinically relevant bacterial strains and their corresponding phages, within which endolysin genes have already been identified. Furthermore, COBIK has expertise in bioprocessing, possesses biological and engineering knowledge needed to develop hydrolases and has skills in biochemical characterization of proteins and antibacterial activity profiling. The University of Ljubljana, Faculty of Pharmacy, Department of Medicinal Chemistry will contribute comprehensive knowledge in drug discovery, including computer-aided drug design, molecular modelling, molecular dynamics simulations, and in silico property prediction. Sferogen, Innovative Biotech LLC will support the project with its advanced biotechnology and protein engineering capabilities, applying its proprietary platform—originally developed for next-generation vaccines—to antibacterial research, thereby providing an innovative technological component to the consortium.
The project is co-funded by the Slovenian Research and Innovation Agency ARIS.
