Enzymatic reshaping of amino acids and nucleosides into antibiotics

Several peptidyl nucleoside antibiotics have been discovered that inhibit bacterial translocase I, a ubiquitous and essential enzyme that initiates the lipid cycle of peptidoglycan cell wall biosynthesis. We are interested in the mechanism of amide bond formation within these antibiotics, a process that is typically mediated by synthetases that use ATP to drive the coupling of amines and carboxylates via formation of an acyl-phosphate or acyl-adenylate intermediate. Capuramycin, a nucleoside antibiotic with potential as an anti-tuberculosis drug, has two amide bonds and two different mechanisms for their formation have been uncovered: a traditional ATP-dependent mechanism and an ATP-independent mechanism that employs a methyl ester as the activated acyl donor. The mechanistic details and progress toward exploiting these amide bond forming strategies to make new capuramycins will be presented.