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β-Lactam antibiotic-degrading enzymes from non-pathogenic marine organisms: a potential threat to human health

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Abstract

Metallo-β-lactamases (MBLs) are a family of Zn(II)-dependent enzymes that inactivate most of the commonly used β-lactam antibiotics. They have emerged as a major threat to global healthcare. Recently, we identified two novel MBL-like proteins, Maynooth IMipenemase-1 (MIM-1) and Maynooth IMipenemase-2 (MIM-2), in the marine organisms Novosphingobium pentaromativorans and Simiduia agarivorans, respectively. Here, we demonstrate that MIM-1 and MIM-2 have catalytic activities comparable to those of known MBLs, but from the pH dependence of their catalytic parameters it is evident that both enzymes differ with respect to their mechanisms, with MIM-1 preferring alkaline and MIM-2 acidic conditions. Both enzymes require Zn(II) but activity can also be reconstituted with other metal ions including Co(II), Mn(II), Cu(II) and Ca(II). Importantly, the substrate preference of MIM-1 and MIM-2 appears to be influenced by their metal ion composition. Since neither N. pentaromativorans nor S. agarivorans are human pathogens, the precise biological role(s) of MIM-1 and MIM-2 remains to be established. However, due to the similarity of at least some of their in vitro functional properties to those of known MBLs, MIM-1 and MIM-2 may provide essential structural insight that may guide the design of as of yet elusive clinically useful MBL inhibitors.

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Acknowledgments

This work was supported in part by a research Grant from Science Foundation Ireland (SFI) under its PIYRA Programme, Grant Number 09/YI/B1756. G. S. acknowledges the award of a Future Fellowship from the Australian research Council (FT120100694) and is grateful to the National Health and Medical Research Council of Australia for funding.

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  1. Department of Chemistry, Maynooth University, Maynooth, Co., Kildare, Ireland

    Manfredi Miraula & Nataša Mitić

  2. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, 4072, Australia

    Manfredi Miraula, Jacob J. Whitaker & Gerhard Schenk

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  1. Manfredi Miraula
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Correspondence to Gerhard Schenk or Nataša Mitić.

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Miraula, M., Whitaker, J.J., Schenk, G. et al. β-Lactam antibiotic-degrading enzymes from non-pathogenic marine organisms: a potential threat to human health. J Biol Inorg Chem 20, 639–651 (2015). https://doi.org/10.1007/s00775-015-1250-x

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