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Metallo-β-lactamases withstand low Zn(II) conditions by tuning metal-ligand interactions

Nature Chemical Biology volume 8, pages 698–700 (2012)Cite this article

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Abstract

A number of multiresistant bacterial pathogens inactivate antibiotics by producing Zn(II)-dependent β-lactamases. We show that metal uptake leading to an active dinuclear enzyme in the periplasmic space of Gram-negative bacteria is ensured by a cysteine residue, an unusual metal ligand in oxidizing environments. Kinetic, structural and affinity data show that such Zn(II)-cysteine interaction is an adaptive trait that tunes the metal binding affinity, thus enabling antibiotic resistance at restrictive Zn(II) concentrations.

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Figure 1: The capacity to confer resistance of BcIIC221D enzyme to E. coli cells is impaired under low Zn(II) conditions.
Figure 2: Structures of the mono- and di-Zn(II) binding sites of BcIIC221D enzyme.
Figure 3: The mono-Co(II) BcIIC221D is inactive and unable to bind the imipenem substrate.

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Acknowledgements

This work has been supported by CONICET and by grants from the Howard Hughes Medical Institute, Agencia Nacional de Promoción Científica y Tecnológica, US National Institutes of Health (1R01AI100560 to A.J.V.) and Laboratório Nacional de Luz Síncrotron, Campinas, Brazil. A.J.V. is a fellow of the John Simon Guggenheim Foundation.

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Author notes

  1. Javier M González & Francisco J Medrano Martín

    Present address: Present addresses: Department of Pharmaceutical Sciences, University of Maryland at Baltimore, Baltimore, Maryland, USA (J.M.G.); University of Maryland Crystallography Shared Service, University of Maryland at Baltimore, Baltimore, Maryland, USA (J.M.G.) and Centro de Investigaciones Biológicas, Madrid, Spain (F.J.M.M.).,

  2. Javier M González and María-Rocío Meini: These authors contributed equally to this work.

Authors and Affiliations

  1. Instituto de Biología Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina

    Javier M González, María-Rocío Meini, Pablo E Tomatis, Julia A Cricco & Alejandro J Vila

  2. Laboratório Nacional de Luz Síncrotron, Sao Paulo, Brazil

    Francisco J Medrano Martín

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  1. Javier M González
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Contributions

J.M.G., J.A.C., M.-R.M., P.E.T. and A.J.V. designed experiments and analyzed results. J.M.G., M.-R.M., P.E.T. and A.J.V. wrote the manuscript. J.M.G., J.A.C. and M.-R.M. expressed and purified proteins. J.M.G. and J.A.C. determined kinetic parameters and performed cobalt substitution. J.M.G. performed stopped-flow measurements. M.-R.M. determined the dissociation constants for Zn(II) by competition experiments and the activity dependence on Zn(II) concentration. J.M.G. and F.J.M.M. determined the crystal structures. J.A.C. designed and made plasmid constructs, determined minimum inhibitory concentrations and performed in vivo antibiotic sensitivity tests. J.A.C. and M.-R.M. performed periplasmic extracts and western blot assays.

Corresponding authors

Correspondence to Julia A Cricco or Alejandro J Vila.

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The authors declare no competing financial interests.

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González, J., Meini, MR., Tomatis, P. et al. Metallo-β-lactamases withstand low Zn(II) conditions by tuning metal-ligand interactions. Nat Chem Biol 8, 698–700 (2012). https://doi.org/10.1038/nchembio.1005

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