Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7

Alexander Bergstrom; Andrew Katko; Zach Adkins; Jessica Hill; Zishuo Cheng; Mia Burnett; Hao Yang; Mahesh Aitha; M. Rachel Mehaffey; Jennifer S. Brodbelt; Kamaleddin H.M.E. Tehrani; Nathaniel I. Martin; Robert A. Bonomo; Richard C. Page; David L. Tierney; Walter Fast; Gerard D. Wright; Michael W. Crowder

doi:10.1021/acsinfecdis.7b00106

Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7

Alexander Bergstrom, Andrew Katko, Zach Adkins, Jessica Hill, Zishuo Cheng, Mia Burnett, Hao Yang, Mahesh Aitha, M. Rachel Mehaffey, Jennifer S. Brodbelt, Kamaleddin H.M.E. Tehrani, Nathaniel I. Martin, Robert A. Bonomo, Richard C. Page, David L. Tierney, Walter Fast, Gerard D. Wright, Michael W. Crowder^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

Abstract

Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, ¹H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations. Our findings reveal that AMA inhibits the MBLs by removal of the active site metal ions required for β-lactam hydrolysis among the most clinically significant MBLs.

Original language	English (US)
Pages (from-to)	135-145
Number of pages	11
Journal	ACS Infectious Diseases
Volume	4
Issue number	2
DOIs	https://doi.org/10.1021/acsinfecdis.7b00106
State	Published - Feb 9 2018

Funding

†Department of Chemistry and Biochemistry, Miami University, 650 East High Street, Oxford, Ohio 45056, United States ⊥Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States #Department of Chemical Biology and Drug Discovery Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands ‡Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, Ohio 44106, United States §Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas, 107 W. Dean Keeton, Austin, Texas 78712, United States ∥Michael G DeGroote Institute for Infectious Disease and Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S4L8, Canada This work was supported by the National Institute of Health (NIH Grants GM111926 and R01GM121714), Miami University, the National Science Foundation (Grant CHM1509285), and the Robert A. Welch Foundation (F-1572 and F-1155). Research reported in this publication was supported in part by the National Institutes of Health (NIH), through the National Institute of Allergy and Infectious Diseases (R01AI100560, R01AI063517, and R01AI072219 to R.A.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study was also supported in part by funds and/or facilities provided by the Cleveland Department of Veterans Affairs, the Veterans Affairs Merit Review Program (Award 1I01BX001974 to R.A.B.), and the Geriatric Research Education and Clinical Center VISN 10 (R.A.B.). Financial support was also provided by Utrecht University and The Netherlands Organization for Scientific Research. The authors thank Seth M. Cohen of the University of California at San Diego for helpful discussions.

Keywords

IMP-7
NDM-1
VIM-2
antibiotic resistance
aspergillomarasmine A
metallo-β-lactamase

ASJC Scopus subject areas

Infectious Diseases

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10.1021/acsinfecdis.7b00106

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Bergstrom, A., Katko, A., Adkins, Z., Hill, J., Cheng, Z., Burnett, M., Yang, H., Aitha, M., Mehaffey, M. R., Brodbelt, J. S., Tehrani, K. H. M. E., Martin, N. I., Bonomo, R. A., Page, R. C., Tierney, D. L., Fast, W., Wright, G. D., & Crowder, M. W. (2018). Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7. ACS Infectious Diseases, 4(2), 135-145. https://doi.org/10.1021/acsinfecdis.7b00106

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title = "Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7",

abstract = "Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, 1H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations. Our findings reveal that AMA inhibits the MBLs by removal of the active site metal ions required for β-lactam hydrolysis among the most clinically significant MBLs.",

keywords = "IMP-7, NDM-1, VIM-2, antibiotic resistance, aspergillomarasmine A, metallo-β-lactamase",

author = "Alexander Bergstrom and Andrew Katko and Zach Adkins and Jessica Hill and Zishuo Cheng and Mia Burnett and Hao Yang and Mahesh Aitha and Mehaffey, \{M. Rachel\} and Brodbelt, \{Jennifer S.\} and Tehrani, \{Kamaleddin H.M.E.\} and Martin, \{Nathaniel I.\} and Bonomo, \{Robert A.\} and Page, \{Richard C.\} and Tierney, \{David L.\} and Walter Fast and Wright, \{Gerard D.\} and Crowder, \{Michael W.\}",

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day = "9",

doi = "10.1021/acsinfecdis.7b00106",

language = "English (US)",

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Bergstrom, A, Katko, A, Adkins, Z, Hill, J, Cheng, Z, Burnett, M, Yang, H, Aitha, M, Mehaffey, MR, Brodbelt, JS, Tehrani, KHME, Martin, NI, Bonomo, RA, Page, RC, Tierney, DL, Fast, W, Wright, GD & Crowder, MW 2018, 'Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7', ACS Infectious Diseases, vol. 4, no. 2, pp. 135-145. https://doi.org/10.1021/acsinfecdis.7b00106

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T1 - Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7

AU - Bergstrom, Alexander

AU - Katko, Andrew

AU - Adkins, Zach

AU - Hill, Jessica

AU - Cheng, Zishuo

AU - Burnett, Mia

AU - Yang, Hao

AU - Aitha, Mahesh

AU - Mehaffey, M. Rachel

AU - Brodbelt, Jennifer S.

AU - Tehrani, Kamaleddin H.M.E.

AU - Martin, Nathaniel I.

AU - Bonomo, Robert A.

AU - Page, Richard C.

AU - Tierney, David L.

AU - Fast, Walter

AU - Wright, Gerard D.

AU - Crowder, Michael W.

PY - 2018/2/9

Y1 - 2018/2/9

N2 - Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, 1H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations. Our findings reveal that AMA inhibits the MBLs by removal of the active site metal ions required for β-lactam hydrolysis among the most clinically significant MBLs.

AB - Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, 1H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations. Our findings reveal that AMA inhibits the MBLs by removal of the active site metal ions required for β-lactam hydrolysis among the most clinically significant MBLs.

KW - IMP-7

KW - NDM-1

KW - VIM-2

KW - antibiotic resistance

KW - aspergillomarasmine A

KW - metallo-β-lactamase

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M3 - Article

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AN - SCOPUS:85041713470

SN - 2373-8227

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SP - 135

EP - 145

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 2

ER -

Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7

Abstract

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Keywords

ASJC Scopus subject areas

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