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Title: Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity

Abstract

Use and misuse of antibiotics have driven the evolution of serine β-lactamases to better recognize new generations of β-lactam drugs, but the selective pressures driving evolution of metallo-β-lactamases are less clear. Here in this paper, we present evidence that New Delhi metallo-β-lactamase (NDM) is evolving to overcome the selective pressure of zinc(II) scarcity. Studies of NDM-1, NDM-4 (M154L), and NDM-12 (M154L, G222D) demonstrate that the point mutant M154L, contained in 50% of clinical NDM variants, selectively enhances resistance to the penam ampicillin at low zinc(II) concentrations relevant to infection sites. Each of the clinical variants is shown to be progressively more thermostable and to bind zinc(II) more tightly than NDM-1, but a selective enhancement of penam turnover at low zinc(II) concentrations indicates that most of the improvement derives from catalysis rather than stability. X-ray crystallography of NDM-4 and NDM-12, as well as bioinorganic spectroscopy of dizinc(II), zinc(II)/cobalt(II), and dicobalt(II) metalloforms probe the mechanism of enhanced resistance and reveal perturbations of the dinuclear metal cluster that underlie improved catalysis. Lastly, these studies support the proposal that zinc(II) scarcity, rather than changes in antibiotic structure, is driving the evolution of new NDM variants in clinical settings.

Authors:
 [1];  [2];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [4];  [3]; ORCiD logo [3]; ORCiD logo [3]; ORCiD logo [5]; ORCiD logo [1]
  1. Univ. of Texas, Austin, TX (United States). Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, and the LaMontagne Center for Infectious Disease
  2. Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH (United States). Research Services
  3. Miami University, Oxford, OH (United States). Department of Chemistry and Biochemistry
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biology Consortium, Beamline 4.2.2, Advanced Light Source
  5. Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH (United States). Research Services ; Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics, and the CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, OH (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1426739
Grant/Contract Number:  
AC02-05CH11231; AC03-76SF00098
Resource Type:
Accepted Manuscript
Journal Name:
ACS Infectious Diseases
Additional Journal Information:
Journal Volume: 3; Journal Issue: 12; Journal ID: ISSN 2373-8227
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; antibiotic resistance; evolution; nutritional immunity; zinc; β-lactamase

Citation Formats

Stewart, Alesha C., Bethel, Christopher R., VanPelt, Jamie, Bergstrom, Alex, Cheng, Zishuo, Miller, Callie G., Williams, Cameron, Poth, Robert, Morris, Matthew, Lahey, Olivia, Nix, Jay C., Tierney, David L., Page, Richard C., Crowder, Michael W., Bonomo, Robert A., and Fast, Walter. Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity. United States: N. p., 2017. Web. doi:10.1021/acsinfecdis.7b00128.
Stewart, Alesha C., Bethel, Christopher R., VanPelt, Jamie, Bergstrom, Alex, Cheng, Zishuo, Miller, Callie G., Williams, Cameron, Poth, Robert, Morris, Matthew, Lahey, Olivia, Nix, Jay C., Tierney, David L., Page, Richard C., Crowder, Michael W., Bonomo, Robert A., & Fast, Walter. Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity. United States. doi:10.1021/acsinfecdis.7b00128.
Stewart, Alesha C., Bethel, Christopher R., VanPelt, Jamie, Bergstrom, Alex, Cheng, Zishuo, Miller, Callie G., Williams, Cameron, Poth, Robert, Morris, Matthew, Lahey, Olivia, Nix, Jay C., Tierney, David L., Page, Richard C., Crowder, Michael W., Bonomo, Robert A., and Fast, Walter. Sat . "Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity". United States. doi:10.1021/acsinfecdis.7b00128. https://www.osti.gov/servlets/purl/1426739.
@article{osti_1426739,
title = {Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity},
author = {Stewart, Alesha C. and Bethel, Christopher R. and VanPelt, Jamie and Bergstrom, Alex and Cheng, Zishuo and Miller, Callie G. and Williams, Cameron and Poth, Robert and Morris, Matthew and Lahey, Olivia and Nix, Jay C. and Tierney, David L. and Page, Richard C. and Crowder, Michael W. and Bonomo, Robert A. and Fast, Walter},
abstractNote = {Use and misuse of antibiotics have driven the evolution of serine β-lactamases to better recognize new generations of β-lactam drugs, but the selective pressures driving evolution of metallo-β-lactamases are less clear. Here in this paper, we present evidence that New Delhi metallo-β-lactamase (NDM) is evolving to overcome the selective pressure of zinc(II) scarcity. Studies of NDM-1, NDM-4 (M154L), and NDM-12 (M154L, G222D) demonstrate that the point mutant M154L, contained in 50% of clinical NDM variants, selectively enhances resistance to the penam ampicillin at low zinc(II) concentrations relevant to infection sites. Each of the clinical variants is shown to be progressively more thermostable and to bind zinc(II) more tightly than NDM-1, but a selective enhancement of penam turnover at low zinc(II) concentrations indicates that most of the improvement derives from catalysis rather than stability. X-ray crystallography of NDM-4 and NDM-12, as well as bioinorganic spectroscopy of dizinc(II), zinc(II)/cobalt(II), and dicobalt(II) metalloforms probe the mechanism of enhanced resistance and reveal perturbations of the dinuclear metal cluster that underlie improved catalysis. Lastly, these studies support the proposal that zinc(II) scarcity, rather than changes in antibiotic structure, is driving the evolution of new NDM variants in clinical settings.},
doi = {10.1021/acsinfecdis.7b00128},
journal = {ACS Infectious Diseases},
number = 12,
volume = 3,
place = {United States},
year = {2017},
month = {9}
}

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