Bacterial Drug Design

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Science  22 Jun 2007:
Vol. 316, Issue 5832, pp. 1670
DOI: 10.1126/science.316.5832.1670c

The most effective weapons for fighting bacterial infections are those that bacteria use against each other. One tactic for combating the spread of drug-resistant strains is to use multiple drugs, such as the combination of dalfopristin (a type A streptogramin) and quinupristin (a type B streptogramin). The former blocks an early step in ribosomal protein synthesis, whereas the latter blocks a late step.

Korczynska et al. describe the crystal structure of virginiamycin B lyase (Vgb) in complex with quinupristin (fortuitously, a chock of dalfopristin immobilizes two Vgb molecules in the crystal, but this interaction is without an in vivo correlate). Vgb inactivates the cyclic peptide antibiotic by catalyzing a linearization, and structure-based mutagenesis supports the mechanistic proposal that ring opening occurs not via hydrolysis of an ester but by means of a C-O lyase reaction. The detailed view of quinupristin binding to Vgb is consistent with its versatility in detoxifying natural and semisynthetic type B streptogramins—the known modifications all point into the solvent and away from the active site. A comparison of this complex with that of quinupristin bound to the 50S ribosomal subunit may guide design efforts aimed at reducing its affinity for Vgb without lessening its ardor for the ribosome. — GJC

Proc. Natl. Acad. Sci. U.S.A. 104, 10388 (2007).

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