Synthesis, testing, and computational modeling of pleuromutilin 1,2,3-triazole derivatives in the ribosome

Abstract

Pleuromutilin antimicrobials have given rise to the most recently FDA approved class of antibiotics for systemic human use. In this work, we describe a synthesis, assay, modeling approach to pleuromutilin development for the highly complex bacterial ribosome. Libraries of substituted 1,2,3-triazole derivatives were synthesized at the pleuromutilin C20 position by applying a recent anti-Markovnikov hydroazidation protocol to directly install an azido group, and at the C22 position through established methods. To learn about the interactions of these libraries with the ribosome and assess the potential for subsequent derivatization, an unbiased computational modeling method was used to biochemically rationalize binding modes of the C20 and C22 pleuromutilin derivatives. A pattern emerged where the triazole and its pendant chain, be it off the C20 or C22 position, moved to occupy the space vacated by the C22 sulfide group of clinical pleuromutilin compounds. Subsequent activity testing and comparative ranking of the computationally docked derivatives to the in vitro activity results showed a high predictability rating for the C22 substituted compounds. These combined investigations reveal potential restrictions and sites for expansion, paving the way for the development of future pleuromutilin derivates and other ribosome targeting antibiotics.