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Inhibition of CorA-Dependent Magnesium Homeostasis Is Cidal in Mycobacterium tuberculosis
- Source :
- Antimicrobial agents and chemotherapy. 63(10)
- Publication Year :
- 2019
-
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.
- Subjects :
- Microbiology
Mycobacterium tuberculosis
03 medical and health sciences
Structure-Activity Relationship
Bacterial Proteins
Macrophage
Structure–activity relationship
Homeostasis
Pharmacology (medical)
Magnesium
Pathogen
Cation Transport Proteins
Mechanisms of Action: Physiological Effects
030304 developmental biology
Pharmacology
0303 health sciences
biology
030306 microbiology
Chemistry
Drug discovery
Transporter
biology.organism_classification
In vitro
Anti-Bacterial Agents
Infectious Diseases
Pyrimidines
Subjects
Details
- ISSN :
- 10986596
- Volume :
- 63
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Antimicrobial agents and chemotherapy
- Accession number :
- edsair.doi.dedup.....3fd4214f8a3885afb190c73901daff33