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:
-
- Univ. of Texas, Austin, TX (United States). Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, and the LaMontagne Center for Infectious Disease
- Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH (United States). Research Services
- Miami University, Oxford, OH (United States). Department of Chemistry and Biochemistry
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biology Consortium, Beamline 4.2.2, Advanced Light Source
- 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. https://doi.org/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. https://doi.org/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}
}
Web of Science
Works referenced in this record:
Characterization of a New Metallo- -Lactamase Gene, blaNDM-1, and a Novel Erythromycin Esterase Gene Carried on a Unique Genetic Structure in Klebsiella pneumoniae Sequence Type 14 from India
journal, September 2009
- Yong, D.; Toleman, M. A.; Giske, C. G.
- Antimicrobial Agents and Chemotherapy, Vol. 53, Issue 12
NDM-2 carbapenemase in Acinetobacter baumannii from Egypt
journal, March 2011
- Kaase, M.; Nordmann, P.; Wichelhaus, T. A.
- Journal of Antimicrobial Chemotherapy, Vol. 66, Issue 6
Biochemical Analysis of Metallo-β-Lactamase NDM-3 from a Multidrug-Resistant Escherichia coli Strain Isolated in Japan
journal, March 2014
- Tada, Tatsuya; Miyoshi-Akiyama, Tohru; Shimada, Kayo
- Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 6
NDM-4 Metallo-β-Lactamase with Increased Carbapenemase Activity from Escherichia coli
journal, January 2012
- Nordmann, Patrice; Boulanger, Anne E.; Poirel, Laurent
- Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 4
A Novel Variant, NDM-5, of the New Delhi Metallo-β-Lactamase in a Multidrug-Resistant Escherichia coli ST648 Isolate Recovered from a Patient in the United Kingdom
journal, September 2011
- Hornsey, Michael; Phee, Lynette; Wareham, David W.
- Antimicrobial Agents and Chemotherapy, Vol. 55, Issue 12
Identification and molecular characterisation of New Delhi metallo-β-lactamase-1 (NDM-1)- and NDM-6-producing Enterobacteriaceae from New Zealand hospitals
journal, June 2012
- Williamson, Deborah A.; Sidjabat, Hanna E.; Freeman, Joshua T.
- International Journal of Antimicrobial Agents, Vol. 39, Issue 6
Detection of NDM-7 in Germany, a new variant of the New Delhi metallo- -lactamase with increased carbapenemase activity
journal, April 2013
- Gottig, S.; Hamprecht, A. G.; Christ, S.
- Journal of Antimicrobial Chemotherapy, Vol. 68, Issue 8
Novel NDM-9 metallo-β-lactamase identified from a ST107 Klebsiella pneumoniae strain isolated in China
journal, July 2014
- Wang, Xiaojuan; Li, Henan; Zhao, Chunjiang
- International Journal of Antimicrobial Agents, Vol. 44, Issue 1
Presence of a novel variant NDM-10, of the New Delhi metallo-beta-lactamase in a Klebsiella pneumoniae isolate
journal, January 2016
- Khajuria, Atul; Praharaj, Ashok Kumar; Kumar, Mahadevan
- Indian Journal of Medical Microbiology, Vol. 34, Issue 1
NDM-12, a Novel New Delhi Metallo-β-Lactamase Variant from a Carbapenem-Resistant Escherichia coli Clinical Isolate in Nepal
journal, August 2014
- Tada, Tatsuya; Shrestha, Basudha; Miyoshi-Akiyama, Tohru
- Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 10
Identification of a Novel NDM Variant, NDM-13, from a Multidrug-Resistant Escherichia coli Clinical Isolate in Nepal
journal, July 2015
- Shrestha, Basudha; Tada, Tatsuya; Miyoshi-Akiyama, Tohru
- Antimicrobial Agents and Chemotherapy, Vol. 59, Issue 9
A Novel New Delhi Metallo-β-Lactamase Variant, NDM-14, Isolated in a Chinese Hospital Possesses Increased Enzymatic Activity against Carbapenems
journal, February 2015
- Zou, Dayang; Huang, Yong; Zhao, Xiangna
- Antimicrobial Agents and Chemotherapy, Vol. 59, Issue 4
Multiyear, Multinational Survey of the Incidence and Global Distribution of Metallo-β-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa
journal, February 2016
- Kazmierczak, Krystyna M.; Rabine, Sharon; Hackel, Meredith
- Antimicrobial Agents and Chemotherapy, Vol. 60, Issue 2
Plasmid-Mediated Novel bla NDM-17 Gene Encoding a Carbapenemase with Enhanced Activity in a Sequence Type 48 Escherichia coli Strain
journal, May 2017
- Liu, Zhihai; Wang, Yang; Walsh, Timothy R.
- Antimicrobial Agents and Chemotherapy, Vol. 61, Issue 5
B1-Metallo-β-Lactamases: Where Do We Stand?
journal, May 2016
- F. Mojica, Maria; A. Bonomo, Robert; Fast, Walter
- Current Drug Targets, Vol. 17, Issue 9
Epidemiological Expansion, Structural Studies, and Clinical Challenges of New β-Lactamases from Gram-Negative Bacteria
journal, October 2011
- Bush, Karen; Fisher, Jed F.
- Annual Review of Microbiology, Vol. 65, Issue 1
The Drug-Resistant Variant P167S Expands the Substrate Profile of CTX-M β-Lactamases for Oxyimino-Cephalosporin Antibiotics by Enlarging the Active Site upon Acylation
journal, June 2017
- Patel, Meha P.; Hu, Liya; Stojanoski, Vlatko
- Biochemistry, Vol. 56, Issue 27
Biochemical characterization of New Delhi metallo-β-lactamase variants reveals differences in protein stability
journal, October 2014
- Makena, Anne; Brem, Jürgen; Pfeffer, Inga
- Journal of Antimicrobial Chemotherapy, Vol. 70, Issue 2
Transition Metals and Virulence in Bacteria
journal, November 2016
- Palmer, Lauren D.; Skaar, Eric P.
- Annual Review of Genetics, Vol. 50, Issue 1
Microbial Iron Acquisition: Marine and Terrestrial Siderophores
journal, October 2009
- Sandy, Moriah; Butler, Alison
- Chemical Reviews, Vol. 109, Issue 10
Nutritional immunity: transition metals at the pathogen–host interface
journal, July 2012
- Hood, M. Indriati; Skaar, Eric P.
- Nature Reviews Microbiology, Vol. 10, Issue 8
Femtomolar Sensitivity of Metalloregulatory Proteins Controlling Zinc Homeostasis
journal, June 2001
- Outten, C. E.
- Science, Vol. 292, Issue 5526
Zn(II) Binding to Escherichia coli 70S Ribosomes
journal, November 2011
- Hensley, M. Patrick; Tierney, David L.; Crowder, Michael W.
- Biochemistry, Vol. 50, Issue 46
Beyond iron: non-classical biological functions of bacterial siderophores
journal, January 2015
- Johnstone, Timothy C.; Nolan, Elizabeth M.
- Dalton Transactions, Vol. 44, Issue 14
Crystal structure of NDM-1 reveals a common β-lactam hydrolysis mechanism
journal, August 2011
- Zhang, HongMin; Hao, Quan
- The FASEB Journal, Vol. 25, Issue 8
Spectroscopic and Mechanistic Studies of Heterodimetallic Forms of Metallo-β-lactamase NDM-1
journal, May 2014
- Yang, Hao; Aitha, Mahesh; Marts, Amy R.
- Journal of the American Chemical Society, Vol. 136, Issue 20
Flexible Metal Binding of the Metallo-β-lactamase Domain: Glyoxalase II Incorporates Iron, Manganese, and Zinc in Vivo †
journal, October 2003
- Schilling, Oliver; Wenzel, Nathan; Naylor, Melissa
- Biochemistry, Vol. 42, Issue 40
Metal Content of Metallo-β-lactamase L1 Is Determined by the Bioavailability of Metal Ions
journal, July 2008
- Hu, Zhenxin; Gunasekera, Thusitha S.; Spadafora, Lauren
- Biochemistry, Vol. 47, Issue 30
Use of ferrous iron by metallo-β-lactamases
journal, October 2016
- Cahill, Samuel T.; Tarhonskaya, Hanna; Rydzik, Anna M.
- Journal of Inorganic Biochemistry, Vol. 163
Characterization of Purified New Delhi Metallo-β-lactamase-1
journal, November 2011
- Thomas, Pei W.; Zheng, Min; Wu, Shanshan
- Biochemistry, Vol. 50, Issue 46
Sputum zinc concentration and clinical outcome in older asthmatics: Asthma and sputum zinc concentrations
journal, March 2011
- Jayaram, Lata; Chunilal, Sanjeev; Pickering, Sandy
- Respirology, Vol. 16, Issue 3
The Human Urine Metabolome
journal, September 2013
- Bouatra, Souhaila; Aziat, Farid; Mandal, Rupasri
- PLoS ONE, Vol. 8, Issue 9
Sputum Trace Metals Are Biomarkers of Inflammatory and Suppurative Lung Disease
journal, March 2010
- Gray, Robert D.; Duncan, Andrew; Noble, Donald
- Chest, Vol. 137, Issue 3
Elevated metal concentrations in the CF airway correlate with cellular injury and disease severity
journal, May 2014
- Smith, Daniel J.; Anderson, Gregory J.; Bell, Scott C.
- Journal of Cystic Fibrosis, Vol. 13, Issue 3
Metallo-β-lactamases withstand low Zn(II) conditions by tuning metal-ligand interactions
journal, June 2012
- González, Javier M.; Meini, María-Rocío; Tomatis, Pablo E.
- Nature Chemical Biology, Vol. 8, Issue 8
Membrane anchoring stabilizes and favors secretion of New Delhi metallo-β-lactamase
journal, May 2016
- González, Lisandro J.; Bahr, Guillermo; Nakashige, Toshiki G.
- Nature Chemical Biology, Vol. 12, Issue 7
Carbonic anhydrase II-based metal ion sensing: Advances and new perspectives
journal, February 2010
- Hurst, Tamiika K.; Wang, Da; Thompson, Richard B.
- Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1804, Issue 2
An altered zinc-binding site confers resistance to a covalent inactivator of New Delhi metallo-beta-lactamase-1 (NDM-1) discovered by high-throughput screening
journal, June 2013
- Thomas, Pei W.; Spicer, Timothy; Cammarata, Michael
- Bioorganic & Medicinal Chemistry, Vol. 21, Issue 11
A chromogenic cephalosporin for β-lactamase inhibitor screening assays
journal, September 2012
- Yu, Sophia; Vosbeek, Amy; Corbella, Katherine
- Analytical Biochemistry, Vol. 428, Issue 2
Targeting metallo-carbapenemases via modulation of electronic properties of cephalosporins
journal, November 2014
- Yang, Hao; Young, Heather; Yu, Sophia
- Biochemical Journal, Vol. 464, Issue 2
Substrate-activated Zinc Binding of Metallo-β-lactamases: PHYSIOLOGICAL IMPORTANCE OF THE MONONUCLEAR ENZYMES
journal, April 2002
- Wommer, Sandra; Rival, Sandrine; Heinz, Uwe
- Journal of Biological Chemistry, Vol. 277, Issue 27
Metal Content and Localization during Turnover in B. cereus Metallo-β-lactamase
journal, November 2008
- Llarrull, Leticia I.; Tioni, Mariana F.; Vila, Alejandro J.
- Journal of the American Chemical Society, Vol. 130, Issue 47
Molar absorption coefficients and stability constants of metal complexes of 4-(2-pyridylazo)resorcinol (PAR): Revisiting common chelating probe for the study of metalloproteins
journal, November 2015
- Kocyła, Anna; Pomorski, Adam; Krężel, Artur
- Journal of Inorganic Biochemistry, Vol. 152
Structural Influence of Hydrophobic Core Residues on Metal Binding and Specificity in Carbonic Anhydrase II † , ‡
journal, November 2000
- Cox, J. David; Hunt, Jennifer A.; Compher, Kevin M.
- Biochemistry, Vol. 39, Issue 45
Nuclear magnetic resonance of paramagnetic metalloproteins
journal, December 1993
- Bertini, Ivano; Turano, Paola; Vila, Alejandro J.
- Chemical Reviews, Vol. 93, Issue 8
Trapping and Characterization of a Reaction Intermediate in Carbapenem Hydrolysis by B. cereus Metallo-β-lactamase
journal, November 2008
- Tioni, Mariana F.; Llarrull, Leticia I.; Poeylaut-Palena, Andrés A.
- Journal of the American Chemical Society, Vol. 130, Issue 47
Efficacies of calcium–EDTA in combination with imipenem in a murine model of sepsis caused by Escherichia coli with NDM-1 β-lactamase
journal, January 2013
- Yoshizumi, Ayumi; Ishii, Yoshikazu; Kimura, Soichiro
- Journal of Infection and Chemotherapy, Vol. 19, Issue 5
Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance
journal, June 2014
- King, Andrew M.; Reid-Yu, Sarah A.; Wang, Wenliang
- Nature, Vol. 510, Issue 7506
Crystal structure of New Delhi metallo-β-lactamase reveals molecular basis for antibiotic resistance
journal, August 2011
- King, Dustin; Strynadka, Natalie
- Protein Science, Vol. 20, Issue 9
The Role of Residue 238 of TEM-1 β-Lactamase in the Hydrolysis of Extended-spectrum Antibiotics
journal, October 1998
- Cantu, Carlos; Palzkill, Timothy
- Journal of Biological Chemistry, Vol. 273, Issue 41
Early Dissemination of NDM-1- and OXA-181-Producing Enterobacteriaceae in Indian Hospitals: Report from the SENTRY Antimicrobial Surveillance Program, 2006-2007
journal, December 2010
- Castanheira, Mariana; Deshpande, Lalitagauri M.; Mathai, Dilip
- Antimicrobial Agents and Chemotherapy, Vol. 55, Issue 3
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
Optimal description of a protein structure in terms of multiple groups undergoing TLS motion
journal, March 2006
- Painter, Jay; Merritt, Ethan A.
- Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 4
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
Frequency-Switching Inversion-Recovery for Severely Hyperfine-Shifted NMR: Evidence of Asymmetric Electron Relaxation in High-Spin Co(II)
journal, November 2006
- Riley, Erin A.; Petros, Amy K.; Smith, Karen Ann
- Inorganic Chemistry, Vol. 45, Issue 25
New Delhi Metallo-β-Lactamase: Structural Insights into β-Lactam Recognition and Inhibition
journal, July 2012
- King, Dustin T.; Worrall, Liam J.; Gruninger, Robert
- Journal of the American Chemical Society, Vol. 134, Issue 28
Polder maps: improving OMIT maps by excluding bulk solvent
journal, February 2017
- Liebschner, Dorothee; Afonine, Pavel V.; Moriarty, Nigel W.
- Acta Crystallographica Section D Structural Biology, Vol. 73, Issue 2, p. 148-157
Works referencing / citing this record:
The antimicrobial peptide thanatin disrupts the bacterial outer membrane and inactivates the NDM-1 metallo-β-lactamase
journal, August 2019
- Ma, Bo; Fang, Chao; Lu, Linshan
- Nature Communications, Vol. 10, Issue 1
Evolution of New Delhi metallo-β-lactamase (NDM) in the clinic: Effects of NDM mutations on stability, zinc affinity, and mono-zinc activity
journal, June 2018
- Cheng, Zishuo; Thomas, Pei W.; Ju, Lincheng
- Journal of Biological Chemistry, Vol. 293, Issue 32
A Single Salt Bridge in VIM-20 Increases Protein Stability and Antibiotic Resistance under Low-Zinc Conditions
journal, November 2019
- Cheng, Zishuo; Shurina, Ben A.; Bethel, Christopher R.
- mBio, Vol. 10, Issue 6
Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases
journal, May 2019
- Chen, Allie Y.; Thomas, Pei W.; Cheng, Zishuo
- ChemMedChem, Vol. 14, Issue 13