Synthetic biology of modular phage proteins

Yves Briers

Yves Briers

Ghent University

Laboratory of Applied Biotechnology

Yves Briers is an Associate Professor and head of the Laboratory of Applied Biotechnology at the department of Biotechnology of Ghent University (Belgium). The research interests of his group focus on the synthetic biology of modular proteins with a particular focus of phage proteins such as lysins and phage receptor-binding proteins. He co-founded the Belgian Society for Viruses of Microbiology in 2022. Last year in summer 2023 he founded the spinoff Obulytix that develops phage lysins for human therapy.

Authors: Briers Y1

Affiliations: (1). Laboratory of Applied Biotechnology, Department of Biotechnology, Ghent University, Ghent (Belgium)

Bacteriophages drive an unparalleled evolutionary arms race. Their short replication cycles and rapid turnover accelerate protein evolution in phages far beyond any other known system. Our research group has a keen interest in two highly modular phage proteins, lysins and receptor-binding proteins (RBPs), which are characterized by frequent recombination. For phage lysins, we have developed a comprehensive pipeline, inspired by hit-to-lead strategies in small molecule drug discovery. This pipeline integrates design-build-test-learn cycles, spanning from discovery (via the PhaLP database 2.0, http://phalp.ugent.be), and (meta)genomic prediction and analysis tools like SUBLYME and SPAED) to high-througput lysin engineering. This approach has yielded engineered lysins with enhanced functionality under harsh conditions that have been evaluated for diverse applications. In parallel, we aim to advance the field of RBPs with a similarly comprehensive pipeline, starting with community tools, including the novel PhaRBP database (http://pharbp.ugent.be), which integrates in-house developed tools with others for RBP/depolymerase detection, and PhageHostLearn for specificity prediction. We have dissected the modular architecture of complex RBPs in Klebsiella phages at both phage and protein level. These insights directed a standardized strategy for engineering Klebsiella phages and tailocins with branched RBPs, enabling cross-genus targeting capabilities. Our integrated approach to phage protein discovery and engineering not only deepens our understanding of phage biology but also paves the way for next-generation biocontrol agents.