The University of Shizuoka discovers new enzyme which enhances antibiotic activity

A research group comprising Graduate Students Hikari Ozawa and Azusa Miyata from the Graduate School of Integrated Pharmaceutical and Nutritional Sciences at the University of Shizuoka, Professor Noriyuki Miyoshi, Associate Professor Sohei Ito, and Research Assistant Professor Daisuke Fujinami from the School of Food and Nutritional Sciences at the University of Shizuoka, and Postdoctoral Research Fellow Seiichiro Hayashi and Professor Koichi Kato from the Exploratory Research Center on Life and Living Systems (ExCELLS) at the Institute for Molecular Science announced the discovery of a new enzyme, "PalQ," which enhances antibiotic activity. This is expected to serve as a new foundation for antimicrobial drug development and peptide drug discovery. The results were published in the Journal of the American Chemical Society on July 13.

Due to the increase in drug-resistant bacteria that are unresponsive to antibiotics, infections that are difficult to treat are increasing, resulting in over one million deaths worldwide annually. While the discovery of new antibiotics and their clinical application are urgently needed, many candidate compounds face difficulties in practical implementation.

To break through this current situation, technologies that enhance functions such as antimicrobial activity and stability by adding chemical or enzymatic modifications to existing antibiotics are attracting attention.

In this study, the researchers achieved lipid modification of antimicrobial peptides using the newly discovered enzyme "PalQ" through careful examination of microbial genetic information.

PalQ catalyzes the reaction (prenylation) that transfers prenyl groups (a type of lipid with isoprene units C₅H₈ as the basic skeleton) to tryptophan residues of antimicrobial peptides. Using PalQ, the group examined combinations of nine types of antimicrobial peptides, including Plantaricin A and PA-Win, with prenyl groups.

As a result, they successfully achieved an 18-fold improvement in antimicrobial activity for Plantaricin A and a 15-fold improvement for PA-Win when tryptophan at the peptide terminus was modified with medium-length prenyl groups. Molecular dynamics simulations revealed that this activity enhancement was due to the interaction between prenyl groups and cell membranes.

Furthermore, through AI-assisted structural optimization, they successfully conferred organic solvent resistance to PalQ and expanded the types of antimicrobial peptide to which it is applicable.

This is expected to serve as a new foundation for antimicrobial drug development and peptide drug discovery.

Fujinami commented: "While proteins are composed of only 20 limited amino acids, we challenged ourselves to artificially expand their chemical diversity by utilizing enzymes found in nature. In the future, we hope to work on designing new proteins by combining human intuition with AI innovation."

Journal Information
Publication: Journal of the American Chemical Society
Title: Expanding the Chemical Space of Antimicrobial Peptides via Enzymatic Prenylation
DOI: 10.1021/jacs.5c06850