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Class D β-lactamases do exist in Gram-positive bacteria

Nature Chemical Biology volume 12, pages 9–14 (2016)Cite this article

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Abstract

Production of β-lactamases of one of four molecular classes (A, B, C and D) is the major mechanism of bacterial resistance to β-lactams, the largest class of antibiotics, which have saved countless lives since their inception 70 years ago. Although several hundred efficient class D enzymes have been identified in Gram-negative pathogens over the last four decades, none have been reported in Gram-positive bacteria. Here we demonstrate that efficient class D β-lactamases capable of hydrolyzing a wide array of β-lactam substrates are widely disseminated in various species of environmental Gram-positive organisms. Class D enzymes of Gram-positive bacteria have a distinct structural architecture and employ a unique substrate-binding mode that is quite different from that of all currently known class A, C and D β-lactamases. These enzymes thus constitute a previously unknown reservoir of novel antibiotic-resistance enzymes.

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Figure 1: The BPU-1 structure.
Figure 2: Structure-based sequence alignment of Gram-positive class D β-lactamases.
Figure 3: BPU-1 substrate binding.

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Protein Data Bank

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GenBank/EMBL/DDBJ

NCBI Reference Sequence

Protein Data Bank

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Acknowledgements

The Stanford Synchrotron Radiation Lightsource (SSRL) is a national user facility operated by Stanford University and supported by the US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the US National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS) (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

    Marta Toth, Nuno Tiago Antunes, Nichole K Stewart, Hilary Frase, Monolekha Bhattacharya & Sergei B Vakulenko

  2. Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, California, USA

    Clyde A Smith

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Contributions

S.B.V. and N.T.A. performed the genomic sequence screening and sequence alignments; M.T., N.T.A., N.K.S., M.B. and H.F. designed and performed the microbiological and kinetic experiments and analyzed the resulting data; M.T., N.T.A. and C.A.S. designed and performed the crystallography experiments; C.A.S. collected and analyzed the crystallographic data; S.B.V. and C.A.S. wrote the manuscript.

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Correspondence to Clyde A Smith or Sergei B Vakulenko.

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Toth, M., Antunes, N., Stewart, N. et al. Class D β-lactamases do exist in Gram-positive bacteria. Nat Chem Biol 12, 9–14 (2016). https://doi.org/10.1038/nchembio.1950

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