A VersaTile-driven platform for rapid hit-to-lead development of engineered lysins

Area of Science:

• Microbiology
• Biotechnology
• Drug Discovery

Background:

• The rise of antibiotic-resistant bacteria necessitates novel antibacterial strategies.
• Bacteriophage-encoded lysins represent a promising class of antimicrobials with significant therapeutic potential.
• Custom engineering of lysins offers a versatile approach to target diverse bacterial pathogens.

Purpose of the Study:

• To present a high-throughput hit-to-lead development platform for engineered lysins.
• To rapidly construct and screen a large library of engineered lysin variants.
• To identify potent lysin variants effective against challenging bacterial infections.

Main Methods:

• Development of the VersaTile DNA assembly method for combinatorial library construction.
• Generation of approximately 10,000 engineered lysin variants.
• Iterative screening procedures to identify lead antibacterial candidates.

Main Results:

• Identification of a lead lysin variant with potent antibacterial activity against Acinetobacter baumannii.
• Demonstration of efficacy in human serum and an ex vivo pig burn wound model.
• Validation of the platform's capability for rapid development of therapeutic lysins.

Conclusions:

• The developed platform enables high-throughput generation and screening of engineered lysins.
• The identified lead variant shows significant potential for treating Acinetobacter baumannii infections.
• This generic platform can accelerate the preclinical development of novel lysin-based antibacterials for various applications.