Total Synthesis of Paenitracin B and Analogues with Enhanced Antibacterial Activity.

Abstract

The development of antibacterials with unique mechanisms of action is key to addressing the threat posed by antibiotic resistance. Among the wide array of natural products that target bacterial cell wall biosynthesis, bacitracin A is the preeminent example of an antibiotic that functions by selectively targeting and sequestering the key bacterial phospholipid undecaprenyl pyrophosphate (C55PP). Historically, the bacitracins have been isolated from fermentations of Bacillus species. We recently discovered a series of structurally distinct bacitracin-like peptide antibiotics produced by members of the Paenibacillus genus, termed the paenitracins. Here, we report the total synthesis of paenitracin B (1), enabling definitive stereochemical validation of the previously proposed structure and delivering quantities of material suitable for more extensive antibacterial testing. The synthetic route developed was also applied to the preparation of paenitracin analogues, with some showing significantly enhanced antibacterial activity, particularly against VanA-type vancomycin-resistant Enterococcus faecium clinical isolates.