Beyond Antibiotics: Unravelling A Death Mechanism of Superbugs by Nanoengineered Star Peptide Polymers through Molecular Simulation and Experiment

Multi-drug resistant (MDR) bacteria pose a significant threat to global health and the economy, with staggering statistics revealing the severity of the issue. A recently synthesized class of polymers, so-called Structurally Nanoengineered Anti-Microbial Peptide Polymers (SNAPPs) composed of arms made of amino acid residues have shown to display superior antibacterial performance against gram negative and gram positive bacteria compared to traditional antibiotics. Despite laboratory experiments confirming SNAPP's effectiveness in killing bacteria, the molecular mechanisms responsible for the kill mechanism and therefore corresponding control parameters are yet to be fully understood. Molecular dynamics (MD) simulation is a powerful technique that enables direct studies of molecular scale interactions among SNAPPs and bacterial cell envelope. MD also allows to establish the complex linkages between SNAPPS’s chemical structure parameters and its antibacterial performance indicators, paving the way to optimise SNAPP’s chemical structure for maximum performance through machine learning and statistical optimization.

Through MD simulations of interaction of SNAPP composed of valine and lysine residues in its arms, we established step-by-step pore forming mechanism which leads to bacteria cell death. The mechansim was further validated through laboratory experiment in vivo.