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Mechanisms of Action: Physiological Effects

Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals

Richard J. Wall, Sonia Moniz, Michael G. Thomas, Suzanne Norval, Eun-Jung Ko, Maria Marco, Timothy J. Miles, Ian H. Gilbert, David Horn, Alan H. Fairlamb, Susan Wyllie
Richard J. Wall
aWellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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Sonia Moniz
aWellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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Michael G. Thomas
aWellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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Suzanne Norval
aWellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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Eun-Jung Ko
aWellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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Maria Marco
bDiseases of the Developing World, GlaxoSmithKline, Madrid, Spain
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Timothy J. Miles
bDiseases of the Developing World, GlaxoSmithKline, Madrid, Spain
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Ian H. Gilbert
aWellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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David Horn
aWellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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Alan H. Fairlamb
aWellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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Susan Wyllie
aWellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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DOI: 10.1128/AAC.00235-18
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ABSTRACT

The lack of information regarding the mechanisms of action (MoA) or specific molecular targets of phenotypically active compounds can prove a barrier to their development as chemotherapeutic agents. Here, we report the results of our orthogonal genetic, molecular, and biochemical studies to determine the MoA of a novel 7-substituted 8-hydroxy-1,6-naphthyridine (8-HNT) series that displays promising activity against Trypanosoma brucei and Leishmania donovani. High-throughput loss-of-function genetic screens in T. brucei highlighted two probable zinc transporters associated with resistance to these compounds. These transporters localized to the parasite Golgi apparatus. Directed by these findings, the role of zinc and other divalent cations in the MoA of these compounds was investigated. 8-HNT compounds were found to directly deplete intracellular levels of Zn2+, while the addition of exogenous Zn2+ and Fe2+ reduced the potency of compounds from this series. Detailed biochemical analyses confirmed that 8-HNT compounds bind directly to a number of divalent cations, predominantly Zn2+, Fe2+, and Cu2+, forming 2:1 complexes with one of these cations. Collectively, our studies demonstrate transition metal depletion, due to chelation, as the MoA of the 8-HNT series of compounds. Strategies to improve the selectivity of 8-HNT compounds are discussed.

FOOTNOTES

    • Received 5 February 2018.
    • Returned for modification 12 March 2018.
    • Accepted 18 May 2018.
    • Accepted manuscript posted online 29 May 2018.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00235-18.

  • Copyright © 2018 Wall et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals
Richard J. Wall, Sonia Moniz, Michael G. Thomas, Suzanne Norval, Eun-Jung Ko, Maria Marco, Timothy J. Miles, Ian H. Gilbert, David Horn, Alan H. Fairlamb, Susan Wyllie
Antimicrobial Agents and Chemotherapy Jul 2018, 62 (8) e00235-18; DOI: 10.1128/AAC.00235-18

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Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals
Richard J. Wall, Sonia Moniz, Michael G. Thomas, Suzanne Norval, Eun-Jung Ko, Maria Marco, Timothy J. Miles, Ian H. Gilbert, David Horn, Alan H. Fairlamb, Susan Wyllie
Antimicrobial Agents and Chemotherapy Jul 2018, 62 (8) e00235-18; DOI: 10.1128/AAC.00235-18
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KEYWORDS

chelator
drug discovery
kinetoplastids
mechanisms of action
transition metals

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