J. Am. Chem. Soc. 133, 13946–13949 (2011)

Vancomycin is used as the 'drug of last resort' in methicillin-resistant Staphylococcus aureus, and yet other bacteria are increasingly resistant to this glycopeptide antibiotic, posing a major problem for human health. Vancomycin activity results from binding to a D-Ala-D-Ala sequence within bacterial peptidoglycan; resistant bacteria use late-stage remodeling of this sequence to D-Ala-D-Lac—converting an amide bond to an ester bond—to circumvent vancomycin's effects. This single-atom change by the bacteria causes the loss of a hydrogen bond and the introduction of charge repulsion between this oxygen and the carbonyl group of residue 4 in the vancomycin scaffold. Crowley and Boger have previously shown that removal of the carbonyl somewhat allays these problems, improving both binding to the D-Ala-D-Lac sequence and activity against relevant resistant bacteria, but the overall change in activity was somewhat limited. Xie et al. now introduce a nitrogen to this same position to more directly compensate for the bacterial change. The careful conversion of a thiolated species to the amidine yielded a compound that almost fully restored binding and activity against resistant bacteria yet maintained a comparable level of activity against wild-type strains. These results provide a new strategy for antimicrobial drug discovery and add to our limited understanding of amidine as an amide isostere.