Electrostatic-Mediated Affinity Tuning of Lysostaphin Accelerates Bacterial Lysis Kinetics and Enhances in Vivo Efficacy.

Electrostatic-Mediated Affinity Tuning of Lysostaphin Accelerates Bacterial Lysis Kinetics and Enhances in Vivo Efficacy.
Antimicrob Agents Chemother. 2021 Jan 19;:
Authors: Zhao H, Eszterhas S, Furlon J, Cheng H, Griswold KE
Abstract
Drug-resistant bacterial pathogens are a serious threat to global health, and antibacterial lysins are at the forefront of innovative treatments for these life-threatening infections. While lysins' general mechanism of action is well understood, the design principles that might enable engineering of performance-enhanced variants are still being formulated. Here we report a detailed analysis of molecular determinants underlying the in vivo efficacy of lysostaphin, a canonical anti-MRSA lysin. Systematic analysis of bacterial binding, growth inhibition, lysis kinetics, and in vivo therapeutic efficacy revealed that binding affinity, and not inherent catalytic firepower, is the dominant driver of lysostaphin efficacy. This insight enabled electrostatic affinity tuning of lysostaphin to produce a single point mutant that manifested dramatically enhanced processivity, lysis kinetics, and trended toward improved in vivo efficacy. More generally these studies provide unprecedented insights into the complex relationships between lysin electrostatics, bacterial targeting, cell lysis efficiency, and in vivo efficacy. The lessons learned may enable engineering of other high-performance antibacterial biocatalysts.
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Source: Antimicrobial Agents and Chemotherapy - January 19, 2021 Category: Microbiology Authors: Zhao H, Eszterhas S, Furlon J, Cheng H, Griswold KE Tags: Antimicrob Agents Chemother Source Type: research