Development of a Natural Product Optimization Strategy for inhibitors against the cell wall synthesis enzyme MraY, a promising antibacterial target

Optimization of natural products is often required to improve their drug-like properties for therapeutic use. However, chemical modifications of natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to clinic. Here, we developed a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We applied this approach to a series of natural product inhibitors for MraY, an important target for the antibacterial development. Through construction and evaluation of the 686-compound library, we identified promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent new types of MraY inhibitors with unique pharmacological profiles.