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

Autor:	Zhao H; Thayer School of Engineering, Dartmouth, Hanover, New Hampshire, USA., Eszterhas S; Thayer School of Engineering, Dartmouth, Hanover, New Hampshire, USA.; Department of Microbiology and Immunology, Dartmouth, Hanover, New Hampshire, USA., Furlon J; Thayer School of Engineering, Dartmouth, Hanover, New Hampshire, USA., Cheng H; Lyticon LLC, Lebanon, New Hampshire, USA., Griswold KE; Thayer School of Engineering, Dartmouth, Hanover, New Hampshire, USA karl.e.griswold@dartmouth.edu.; Department of Biological Sciences, Dartmouth, Hanover, New Hampshire, USA.; Department of Chemistry, Dartmouth, Hanover, New Hampshire, USA.; Lyticon LLC, Lebanon, New Hampshire, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2021 Mar 18; Vol. 65 (4). Date of Electronic Publication: 2021 Mar 18 (Print Publication: 2021).
DOI:	10.1128/AAC.02199-20
Abstrakt:	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 (methicillin-resistant Staphylococcus aureus ) 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 and lysis kinetics and trended toward improved in vivo efficacy. More generally, these studies provide important 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. (Copyright © 2021 American Society for Microbiology.)
Databáze:	MEDLINE
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