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 (Lead / Corresponding author)

Research output: Contribution to journalArticle

Abstract

Mechanisms of magnesium homeostasis in Mycobacterium tuberculosis are poorly understood. Here, we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg 2+/Co 2+ transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg 2+ ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating and nonreplicating 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 Mg 2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.

Original languageEnglish
Article numbere01006-19
Pages (from-to)1-14
Number of pages14
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number10
Early online date5 Aug 2019
DOIs
Publication statusPublished - 23 Sep 2019

Fingerprint

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

Keywords

  • CorA transporter
  • Magnesium homeostasis
  • Mycobacterium tuberculosis
  • Pyrimidinetrione amide
  • Structure-activity relationship

Cite this

Park, Y., Ahn, Y-M., Jonnala, S., Oh, S., Fisher, J. M., Goodwin, M. B., ... Boshoff, H. I. (2019). Inhibition of CorA dependent Magnesium Homeostasis is cidal in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 63(10), 1-14. [e01006-19]. https://doi.org/10.1128/AAC.01006-19
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 ; Vol. 63, No. 10. pp. 1-14.
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abstract = "Mechanisms of magnesium homeostasis in Mycobacterium tuberculosis are poorly understood. Here, we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg 2+/Co 2+ transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg 2+ ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating and nonreplicating 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 Mg 2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.",
keywords = "CorA transporter, Magnesium homeostasis, Mycobacterium tuberculosis, Pyrimidinetrione amide, Structure-activity relationship",
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.}",
note = "This work was funded in part by the Intramural Research Program of NIAID (AI000693-25) and by grants from the Foundation for the National Institutes of Health (BARRY11HTB0) with support from the Bill and Melinda Gates Foundation (OPP1024021).",
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Park, Y, Ahn, Y-M, Jonnala, S, Oh, S, Fisher, JM, Goodwin, MB, Loerger, TR, Via, LE, Bayliss, T, Green, SR, Ray, PC, Wyatt, PG, Barry, CE & Boshoff, HI 2019, 'Inhibition of CorA dependent Magnesium Homeostasis is cidal in Mycobacterium tuberculosis', Antimicrobial Agents and Chemotherapy, vol. 63, no. 10, e01006-19, pp. 1-14. https://doi.org/10.1128/AAC.01006-19

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. (Lead / Corresponding author).

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 10, e01006-19, 23.09.2019, p. 1-14.

Research output: Contribution to journalArticle

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T1 - Inhibition of CorA dependent Magnesium Homeostasis is cidal in Mycobacterium tuberculosis

AU - Park, Yumi

AU - Ahn, Yong-Mo

AU - Jonnala, Surendranadha

AU - Oh, Sangmi

AU - Fisher, Julia M.

AU - Goodwin, Michael B.

AU - Loerger, Thomas R.

AU - Via, Laura E.

AU - Bayliss, Tracy

AU - Green, Simon R.

AU - Ray, Peter C.

AU - Wyatt, Paul G.

AU - Barry, Clifton E.

AU - Boshoff, Helena I.

N1 - This work was funded in part by the Intramural Research Program of NIAID (AI000693-25) and by grants from the Foundation for the National Institutes of Health (BARRY11HTB0) with support from the Bill and Melinda Gates Foundation (OPP1024021).

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N2 - Mechanisms of magnesium homeostasis in Mycobacterium tuberculosis are poorly understood. Here, we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg 2+/Co 2+ transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg 2+ ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating and nonreplicating 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 Mg 2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.

AB - Mechanisms of magnesium homeostasis in Mycobacterium tuberculosis are poorly understood. Here, we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg 2+/Co 2+ transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg 2+ ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating and nonreplicating 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 Mg 2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.

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