Design, Construction, and Screening of a One-Bead-One-Compound Library for Discovery of Potent Analogues of Antibiotic Lysocin E

Abstract

Lysocin E (1), a macrocyclic natural depsipeptide isolated from Lysobacter sp., exerts potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) via a unique menaquinone (MK)-dependent membrane-disrupting mechanism. Here we report design, construction, and screening of a one-bead-one-compound (OBOC) library consisting of thousands of 1 analogues. To find candidate compounds showing more potent antibacterial activity, we integrated total synthesis of 2401 bead-linked macrocyclic peptides, tandem mass spectrometry-based structure determination, on-bead MK-complexation assay, and in-solution antibacterial assay. Re-synthesis and evaluation of the candidate compounds revealed that 11 new analogues exhibit antibacterial activity superior or comparable to that of 1 and MK-dependent membrane disruption.