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)

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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.

Original languageEnglish
Article numbere01006-19
Number of pages14
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number10
Early online date5 Aug 2019
DOIs
Publication statusPublished - 23 Sep 2019

Keywords

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

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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), [e01006-19]. https://doi.org/10.1128/AAC.01006-19