SBIR-STTR Award

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.

Thesaurus Terms:
drug design /synthesis /production, drug discovery /isolation, glycosylation, macrolide antibiotic Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, chemical binding, drug resistance chemical synthesis, laboratory mouse

Respiratory disease remains the primary cause of morbidity and mortality worldwide due to infectious disease such as community acquired respiratory tract infections (RTIs). Beta-lactam or macrolide antibiotics are currently, a first line of treatment for most RTIs, however, a considerable number of pathogens are developing resistance to these current treatments. A primary resistant mechanism of bacteria towards macrolide/ketolide antibiotics is through target modification (rRNA methylation) whereby 5-O-sugar substituent (desosamine) plays a critical role. Under Phase I, unprecedented macrolide medicinal chemistry was successfully developed that enabled the synthesis of novel 5-O-sugar modified ketolide derivatives that displayed excellent activity against macrolide-resistant bacteria. The specific aims of this Phase II proposal are to continue our progress toward identifying a preclinical drug candidate through a series of chemistry lead optimization experiments. The continued medicinal chemistry efforts to improve in vitro and in vivo antibacterial activity will not only be guided by in-house minimum inhibitory concentration (MIC ) determinations (against primary and secondary panels) and in vivo oral efficacy experiments using relevant disease infection models, but in addition, will be guided by computer simulated ligand-receptor docking experiments utilizing computer aided molecular design (CAMD), thus allowing for rational based glycodesigri of our antibacterial analogues. The lead compounds will be further evaluated by obtaining important MIC50/90 data against relevant pathogens (Streptococcus, Haemophilus, and Staphylococcus) and by determining important animal-plasma and -lung pharmacokinetic parameters. Phase II funding will also support studies to determine resistance development and the potential for cross-resistance between our lead compounds and other leading macrolides/ketolides, an important criteria for assessing a compound's future marketability. Finally, preliminary safety will be assessed of our most promising leads by performing mammalian cell cytotoxicity assays and by determining acute oral toxicity in rodents