2. Academic Validation
  3. Inhibition of CorA-Dependent Magnesium Homeostasis Is Cidal in Mycobacterium tuberculosis

Inhibition of CorA-Dependent Magnesium Homeostasis Is Cidal in Mycobacterium tuberculosis

  • Antimicrob Agents Chemother. 2019 Sep 23;63(10):e01006-19. doi: 10.1128/AAC.01006-19.
Yumi Park # 1,  Yong-Mo Ahn # 1,  Surendranadha Jonnala 1,  Sangmi Oh 1,  Julia M Fisher 1,  Michael B Goodwin 1,  Thomas R Ioerger 2,  Laura E Via 1,  Tracy Bayliss 3,  Simon R Green 3,  Peter C Ray 3,  Paul G Wyatt 3,  Clifton E Barry 3rd 1,  Helena I Boshoff 4
Affiliations

Affiliations

  • 1 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
  • 2 Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, USA.
  • 3 Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
  • 4 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA hboshoff@niaid.nih.gov.
  • # Contributed equally.
PMID: 31383669 DOI: 10.1128/AAC.01006-19
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 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 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 Mg2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.

Keywords

CorA transporter; Mycobacterium tuberculosis; magnesium homeostasis; pyrimidinetrione amide; structure-activity relationship.

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