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

doi:10.1128/AAC.01006-19

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 journal › Article › peer-review

9 Citations (Scopus)

143 Downloads (Pure)

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 language	English
Article number	e01006-19
Number of pages	14
Journal	Antimicrobial Agents and Chemotherapy
Volume	63
Issue number	10
Early online date	5 Aug 2019
DOIs	https://doi.org/10.1128/AAC.01006-19
Publication status	Published - 23 Sept 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)
Infectious Diseases

Access to Document

10.1128/AAC.01006-19

Author Accepted ManuscriptAccepted author manuscript, 1.85 MB

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Park, Y., Ahn, Y.-M., Jonnala, S., Oh, S., Fisher, J. M., Goodwin, M. B., Loerger, T. R., Via, L. E., Bayliss, T., Green, S. R., Ray, P. C., Wyatt, P. G., Barry, C. E., & Boshoff, H. I. (2019). Inhibition of CorA dependent Magnesium Homeostasis is cidal in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 63(10), Article e01006-19. https://doi.org/10.1128/AAC.01006-19

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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. 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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doi = "10.1128/AAC.01006-19",

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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).

PY - 2019/9/23

Y1 - 2019/9/23

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.

KW - CorA transporter

KW - Magnesium homeostasis

KW - Mycobacterium tuberculosis

KW - Pyrimidinetrione amide

KW - Structure-activity relationship

UR - https://www.scopus.com/pages/publications/85072570201

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DO - 10.1128/AAC.01006-19

M3 - Article

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SN - 0066-4804

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 10

M1 - e01006-19

ER -

Inhibition of CorA dependent Magnesium Homeostasis is cidal in Mycobacterium tuberculosis

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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