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Published on: January 1, 2016
Enhanced antimicrobial activity of engineered human lysozyme
Thomas C Scanlon1, Charlotte C Teneback, Avinash Gill
1Dartmouth College, Hanover, New Hampshire 03755, USA.
ACS Chemical Biology
|July 8, 2010
Summary
Engineered lysozymes with reduced positive charges show enhanced antibacterial activity against Pseudomonas aeruginosa. Modifying human lysozyme (hLYS) overcomes inhibition by anionic biopolymers found in infections, improving antimicrobial function.
Area of Science:
- Biochemistry
- Microbiology
- Protein Engineering
Background:
- Lysozymes possess cationic residues, attracting them to bacterial surfaces.
- This charge interaction can inhibit lysozyme's antibacterial function during infections due to anionic biopolymer accumulation.
Purpose of the Study:
- To engineer human lysozyme (hLYS) variants with improved antibacterial activity for use as antimicrobial agents.
- To investigate the mechanism of polyanion inhibition of lysozyme and develop strategies to overcome it.
Main Methods:
- Protein engineering of human lysozyme (hLYS) to remodel its electrostatic potential.
- High-throughput screening of charge-engineered hLYS libraries to identify variants with enhanced bactericidal activity.
- Characterization of isolated variants in a mouse model of acute pulmonary Pseudomonas aeruginosa infection.
Main Results:
- Anionic biopolymers in infected lungs correlate with decreased endogenous lysozyme activity.
- Charge-engineered hLYS variants demonstrated improved antibacterial activity in the presence of disease-associated biopolymers.
- One variant exhibited faster bacterial killing kinetics even without inhibitory biopolymers, suggesting a general strategy for enzyme optimization.
Conclusions:
- Decreasing the net cationic character of hLYS enhances its antibacterial activity against Pseudomonas aeruginosa by preventing electrostatic sequestration by anionic biopolymers.
- Protein engineering of lysozymes offers a promising approach to develop novel antimicrobial agents effective in infection environments.
- Tuning the cellular affinity of peptidoglycan hydrolases may be a general strategy to enhance bacterial killing kinetics.
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