Research Project
6738351
Macrolide antibiotics have been marketed since the early 1950's and have a history of being safety and efficacious. These molecules inhibit protein synthesis by interacting with bacterial ribosomal RNA subunits. The recent emergence of macrolide resistance among respiratory tract pathogens has motivated further research in this field. The sugar substituents of the macrolide antibiotics play an important role in both activity and resistance development. In the past, there has been limited work on exploring the sugar binding domains of the macrotides due to inefficient methods available for incorporating novel sugars into the macrolide cores. We propose to apply our new proprietary glycosylation technology, OpopS TM, for introducing novel mono- and di-saccharides into macrolide cores. We hypothesize that by incorporating structural features of the 16-membered macrolide, which are active against the MLS8 resistant phenotype, into a the15-membered macrolides (for example, introducing a disaccharide at the 5-OH position of a 15-membered macrolide), could result in improved activity and lead to a novel hybrid class of macrolide antibiotics. The goal of this proposal is to apply our proprietary gtycosylation technology, OPopS TM, in order to explore the sugar binding domains of the 5-OH and 3-OH positions of macrolides and identify a novel class of macrolide having improved MICs0 and MIC90 activity against clinically relevant resistant pathogens, specifically, Streptococcus pyogenes and Streptococcus pneumoniae, and as well as improved activity against Haemophilus influenzae. The general objectives are to: i) Prepare novel macrolide aglycon cores in order to apply Optimer's proprietary OPopS TM glycosylation technology. ii) Introduce a variety of designer sugars (mono- and di-saccharides) on these new macrolide cores to generate novel macrolide derivatives. iii) Evaluate antimicrobial activities against a panel of clinically relevant pathogens and identify a few promising lead compounds for advancement into in vivo efficacy studies, safety studies, and ultimately clinical development.
