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Structural basis for the β lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus

Nature Structural Biology volume 9, pages 870–876 (2002)Cite this article

Abstract

The multiple antibiotic resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) has become a major clinical problem worldwide. The key determinant of the broad-spectrum β-lactam resistance in MRSA strains is the penicillin-binding protein 2a (PBP2a). Because of its low affinity for β-lactams, PBP2a provides transpeptidase activity to allow cell wall synthesis at β-lactam concentrations that inhibit the β-lactam-sensitive PBPs normally produced by S. aureus. The crystal structure of a soluble derivative of PBP2a has been determined to 1.8 Å resolution and provides the highest resolution structure for a high molecular mass PBP. Additionally, structures of the acyl-PBP complexes of PBP2a with nitrocefin, penicillin G and methicillin allow, for the first time, a comparison of an apo and acylated resistant PBP. An analysis of the PBP2a active site in these forms reveals the structural basis of its resistance and identifies features in newly developed β-lactams that are likely important for high affinity binding.

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Figure 1: Structure of SauPBP2a*.
Figure 2: Interaction of SauPBP2a* with a β-lactam.
Figure 3: Penicillin G-acyl-PBP complex for SauPBP2a*.
Figure 4: Methicillin-acyl-PBP complex for SauPBP2a*.

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Acknowledgements

We thank L.C. Blaszczak and P.L. Skatrud (Infectious Disease Research, Eli Lilly and Company) for providing the initial MRSA strain 27r PBP2a* construct, J. Berendzen and L. Flaks for assistance during data collection at beam line X8-C at the NSLS, S.-M. He for ESMS analysis, Y. Luo and L. De Castro for technical assistance, and M. Bains for DNA sequencing. N.C.J.S. is supported by the Canadian Institutes of Health Research (CIHR), the Howard Hughes Medical Institute (HHMI) and the Canadian Bacterial Diseases Network. N.C.J.S. is a CIHR Investigator, a Burroughs Wellcome New Investigator and a HHMI International Scholar. D.L. is the recipient of a CIHR doctoral research award.

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  1. Department of Biochemistry and Molecular Biology, 2146 Health Sciences Mall, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

    Daniel Lim & Natalie C.J. Strynadka

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Correspondence to Natalie C.J. Strynadka.

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Lim, D., Strynadka, N. Structural basis for the β lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat Struct Mol Biol 9, 870–876 (2002). https://doi.org/10.1038/nsb858

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