Inhibition of CorA dependent Magnesium Homeostasis is cidal in Mycobacterium tuberculosis

Yumi Park, Yong-Mo Ahn, Surendranadha Jonnala, Sangmi Oh, Julia M Fisher, Michael B Goodwin, Thomas R Loerger, Laura E Via, Tracy Bayliss, Simon R Green, Peter C Ray, Paul G Wyatt, Clifton E Barry, Helena I Boshoff

Research output: Contribution to journalArticle

Abstract

Mechanisms of magnesium homeostasis in Mycobacterium tuberculosis are poorly understood. Herein we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg2+/Co2+ transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg2+ ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating as well as non-replicating conditions in vitro and were efficacious against the organism during macrophage infection. However, the compound lacked efficacy in infected mice possibly due to limited exposure. Our results indicate that inhibition of Mg2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.

Original languageEnglish
Number of pages37
JournalAntimicrobial Agents and Chemotherapy
DOIs
Publication statusE-pub ahead of print - 5 Aug 2019

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Mycobacterium tuberculosis
Magnesium
Homeostasis
Amides
Drug Discovery
Tuberculosis
Macrophages
Ions
Mutation
Infection

Cite this

Park, Yumi ; Ahn, Yong-Mo ; Jonnala, Surendranadha ; Oh, Sangmi ; Fisher, Julia M ; Goodwin, Michael B ; Loerger, Thomas R ; Via, Laura E ; Bayliss, Tracy ; Green, Simon R ; Ray, Peter C ; Wyatt, Paul G ; Barry, Clifton E ; Boshoff, Helena I. / Inhibition of CorA dependent Magnesium Homeostasis is cidal in Mycobacterium tuberculosis. In: Antimicrobial Agents and Chemotherapy. 2019.
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title = "Inhibition of CorA dependent Magnesium Homeostasis is cidal in Mycobacterium tuberculosis",
abstract = "Mechanisms of magnesium homeostasis in Mycobacterium tuberculosis are poorly understood. Herein we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg2+/Co2+ transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg2+ ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating as well as non-replicating conditions in vitro and were efficacious against the organism during macrophage infection. However, the compound lacked efficacy in infected mice possibly due to limited exposure. Our results indicate that inhibition of Mg2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.",
author = "Yumi Park and Yong-Mo Ahn and Surendranadha Jonnala and Sangmi Oh and Fisher, {Julia M} and Goodwin, {Michael B} and Loerger, {Thomas R} and Via, {Laura E} and Tracy Bayliss and Green, {Simon R} and Ray, {Peter C} and Wyatt, {Paul G} and Barry, {Clifton E} and Boshoff, {Helena I}",
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Inhibition of CorA dependent Magnesium Homeostasis is cidal in Mycobacterium tuberculosis. / Park, Yumi; Ahn, Yong-Mo; Jonnala, Surendranadha; Oh, Sangmi; Fisher, Julia M; Goodwin, Michael B; Loerger, Thomas R; Via, Laura E; Bayliss, Tracy; Green, Simon R; Ray, Peter C; Wyatt, Paul G; Barry, Clifton E; Boshoff, Helena I.

In: Antimicrobial Agents and Chemotherapy, 05.08.2019.

Research output: Contribution to journalArticle

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AU - Park, Yumi

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AU - Goodwin, Michael B

AU - Loerger, Thomas R

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AU - Ray, Peter C

AU - Wyatt, Paul G

AU - Barry, Clifton E

AU - Boshoff, Helena I

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