CHEMISTRY: Restored Affinity

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Science  17 Feb 2006:
Vol. 311, Issue 5763, pp. 921a
DOI: 10.1126/science.311.5763.921a

Vancomycin is a powerful antibiotic, which functions by binding to a pair of alanine residues and thereby disrupting the formation of bacterial cell walls. However, several strains of bacteria can evolve to resist vancomycin through replacement of the terminal alanine with lactate. This structural substitution of an O atom for an N-H group reduces vancomycin binding affinity by a factor of 1000.

In a preliminary effort to combat this resistance pathway, Crowley and Boger have modified the vancomycin structure. Their prior modeling studies attributed the reduced affinity to lone pair repulsion between the lactate oxygen and a carbonyl oxygen in the vancomycin framework. They therefore prepared a synthetic derivative with a methylene group replacing the offending carbonyl. This backbone substitution was deemed too fundamental a change to attempt by modifying intact vancomycin. Instead, the authors were able to adapt their prior total synthesis of the native compound by introducing the methylene group at the outset and protecting the adjacent nitrogen as a carbamate. The resulting compound showed a 40-fold improvement in activity against cultures of resistant bacteria, with only a 37-fold loss in affinity toward the Ala-Ala motif present in nonresistant strains. — JSY

J. Am. Chem. Soc. 10.1021/ja0572912 (2006).

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