Project information
Physics-based inverse design of new peptides selective for the bacterial peptidoglycan

Bacterial drug resistance poses a public health threat demanding new therapeutic approaches. Endolysins—bacteriophage enzymes that selectively degrade the bacterial protective peptidoglycan (PG) layer—hold significant promise, yet their clinical potential is limited by their size, stability, pharmacokinetics, and incomplete understanding of their binding selectivity. This project will use a new methodological framework for the de novo design of peptides that selectively bind the PG of S. aureus bacteria—including drug-resistant strains—and can guide the endolysins' catalytic domain to their targets. We will develop and validate simulation atomistic models of S. aureus PG using endolysins with known selectivity. We will then employ molecular simulations and evolutionary algorithms for physics-based inverse design of new peptides with tailored affinity, followed by experimental validation using fluorescence microscopy. Project outcomes will advance the molecular understanding of endolysin–PG interactions and yield new peptide scaffolds, paving the way for next-generation enzybiotics.