The University of Tokyo
Talk Title: Development of a Strategy for Discovery of Superior Analogues of Antimicrobial Natural Products
Here we report a novel strategy for the discovery of potent antibiotics by preparing thousands of analogues of a highly complex natural product. Lysocin E, 1, a 37-membered natural peptide, induces rapid bacteriolysis of methicillin-resistant Staphylococcus aureus, MRSA. We designed the one-bead-one-compound approach, in which each bead carried a structurally unique analogue in submicrogram quantity, to produce a 1-based library consisting of 2401 bead-linked cyclic peptides.
By developing a new high throughput method that integrates submicrogram-scale solid-phase total synthesis, split-and-mix randomization, tandem mass spectrometry-sequencing, and miniaturized assays, we determined 26 candidates. Re-synthesis of these candidates in milligram scale disclosed that 11 artificial analogues exhibited antimicrobial activity more potent than or comparable to that of 1. Because of their high potency, newly discovered peptides will serve as highly promising seeds for the development of pharmaceuticals to treat various infectious diseases.
AffiliationsGraduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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