Probing the interaction of Aspergillomarasmine A (AMA) with metallo-β-lactamases NDM-1, VIM-2, and IMP-7

Alexander Bergstrom; Andrew Katko; Zachary B Adkins; Jessica E Hill; Zishuo Cheng; Mia L Burnett; Hao Yang; Mahesh Aitha; M Rachel Mehaffey; Jennifer S Brodbelt; K. Hajmohammadebrahimtehrani; 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 (AMA) with metallo-β-lactamases NDM-1, VIM-2, and IMP-7

Alexander Bergstrom, Andrew Katko, Zachary B Adkins, Jessica E Hill, Zishuo Cheng, Mia L Burnett, Hao Yang, Mahesh Aitha, M Rachel Mehaffey, Jennifer S Brodbelt, K. Hajmohammadebrahimtehrani, 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

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

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
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
Publication status	Published - Feb 2018

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10.1021/acsinfecdis.7b00106

bergstrom-et-al-2017-probing-the-interaction-of-aspergillomarasmine-a-with-metallo-β-lactamases-ndm-1-vim-2-and-imp-7Final published version, 1.42 MBLicence: Taverne

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Bergstrom, A., Katko, A., Adkins, Z. B., Hill, J. E., Cheng, Z., Burnett, M. L., Yang, H., Aitha, M., Mehaffey, M. R., Brodbelt, J. S., Hajmohammadebrahimtehrani, K., 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 (AMA) 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 (AMA) 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.",

author = "Alexander Bergstrom and Andrew Katko and Adkins, {Zachary B} and Hill, {Jessica E} and Zishuo Cheng and Burnett, {Mia L} and Hao Yang and Mahesh Aitha and Mehaffey, {M Rachel} and Brodbelt, {Jennifer S} and K. Hajmohammadebrahimtehrani 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}",

year = "2018",

month = feb,

doi = "10.1021/acsinfecdis.7b00106",

language = "English",

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Bergstrom, A, Katko, A, Adkins, ZB, Hill, JE, Cheng, Z, Burnett, ML, Yang, H, Aitha, M, Mehaffey, MR, Brodbelt, JS, Hajmohammadebrahimtehrani, K, Martin, NI, Bonomo, RA, Page, RC, Tierney, DL, Fast, W, Wright, GD & Crowder, MW 2018, 'Probing the interaction of Aspergillomarasmine A (AMA) 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 (AMA) with metallo-β-lactamases NDM-1, VIM-2, and IMP-7

AU - Bergstrom, Alexander

AU - Katko, Andrew

AU - Adkins, Zachary B

AU - Hill, Jessica E

AU - Cheng, Zishuo

AU - Burnett, Mia L

AU - Yang, Hao

AU - Aitha, Mahesh

AU - Mehaffey, M Rachel

AU - Brodbelt, Jennifer S

AU - Hajmohammadebrahimtehrani, K.

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

Y1 - 2018/2

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.

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DO - 10.1021/acsinfecdis.7b00106

M3 - Article

C2 - 29091730

SN - 2373-8227

VL - 4

SP - 135

EP - 145

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 2

ER -

Probing the interaction of Aspergillomarasmine A (AMA) with metallo-β-lactamases NDM-1, VIM-2, and IMP-7

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