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 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.

• Authors: Yumi Park, Yong-Mo Ahn, Surendranadha Jonnala, Sangmi Oh, Julia M Fisher, Michael B Goodwin, Thomas R Ioerger, Laura E Via, Tracy Bayliss, Simon R Green, Peter C Ray, Paul G Wyatt, Clifton E Barry 3rd, Helena I Boshoff
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 63 Issue 10 (10 2019) ISSN: 1098-6596 [Electronic] United States
• PMID: 31383669 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Society for Microbiology.

Chemical References

• Anti-Bacterial Agents
• Bacterial Proteins
• Cation Transport Proteins
• Pyrimidines
• Magnesium

Topics

• Anti-Bacterial Agents (chemistry, pharmacokinetics, pharmacology)
• Bacterial Proteins (genetics, metabolism)
• Cation Transport Proteins (genetics, metabolism)
• Homeostasis (drug effects)
• Magnesium (metabolism)
• Mycobacterium tuberculosis (drug effects, metabolism)
• Pyrimidines (chemistry, pharmacokinetics, pharmacology)
• Structure-Activity Relationship