Uridyl Peptide Antibiotics: Developments in Biosynthesis and Medicinal Chemistry

The Uridyl-Peptide Antibiotics (UPAs) are a diverse group of bacterial metabolites that are characterized by a uridyl moiety linked to a peptidic residue. Included in this group are the pacidamycins, liposidomycins, capuramycins, and muraymycins. Most of these antibiotics are produced by Streptomyces species and are naturally found as complexes of closely related congeners. The compounds all bear some resemblance to intermediates involved in cell wall biosynthesis in bacteria and exert their antibacterial action through inhibition of the membrane-bound translocase I. Caprazamycin was the first of the UPAs for which a biosynthetic gene cluster was identified and cloned, which quickly led to the discovery of several others. Preliminary experiments have been reported in which biosynthetic insights were applied to the production of analogs for evaluation of antimicrobial activity. Synthetic chemistry has provided evidence for the core features necessary for target inhibition and antibacterial efficacy. Although many of the UPAs have shown potent antibacterial activity, and are effective in inhibiting a highly selective bacterial target, none have progressed to become commercially viable agents. In this chapter, we will explore recent findings that have clarified the promise and limitations of this class of antibiotics.