New sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Herein we discuss the rationale and results derived from our novel desmethylation strategy (i.e., replacing specific methyl groups with hydrogen) for addressing target-based (i.e., ribosomal) mechanisms of resistance, specifically A2058G mutations and erm-mediated N6 methylation of A2058. Said mutations render erythromycin (1  ) and 6-O-methyl congener clarithromycin (2  ) ineffective, in addition to compromising the activity of telithromycin (4  ).  We have prepared various desmethyl congeners of the FDA approved ketolide antibiotic telithromycin (4  ) by total synthesis, evaluated them against various bacterial strains using MIC assays, and performed molecular modeling to better understand the consequences of desmethylation on the macrolactone scaffold. 

Discovery of novel macrolide antibiotics: Synthesis and evaluation of desmethyl analogs of telithromycin

244th National Meeting (2012)

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