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Possible binding orientations ofβ-lactams withinStaphylococcus aureus POβ-lactamase suggest factors involved inβ-lactamase resistance

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Summary

The electrostatic forces within the active site of theβ-lactamaseStaphylococcus aureus PC1 have been used to predict structures for the precatalytic complex with ampicillin, methicillin, clavulanate and imipenem. There are significant differences in the orientation of theseβ-lactams within the binding site, which explains the differences in their resistance to the lactamase. The electrostatic forces were calculated using a distributed multipole analysis ofab initio wave functions for both the lactams and the binding site residues, to ensure a good representation of the orientation dependence of this dominant contribution. The predicted binding orientations are contrasted with those predicted by overlaying the electrostatic extrema around the ligands. The accuracy of the ligand-only-based predictions is limited in some cases because of the subtle steric requirements of the lactamase binding site.

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Authors and Affiliations

  1. Departament de Química (Química-Fisica) Edifici Mateu Orfila, Universitat Illes Balears, 07071, E-Palma de Mallorca, Spain

    J. Frau

  2. Department of Chemistry, University College London, WCIH OAJ, London, UK

    S. L. Price

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  1. J. Frau
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  2. S. L. Price
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Frau, J., Price, S.L. Possible binding orientations ofβ-lactams withinStaphylococcus aureus POβ-lactamase suggest factors involved inβ-lactamase resistance. Theoret. Chim. Acta 95, 151–163 (1996). https://doi.org/10.1007/BF02335462

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