Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, USA.
Antimicrob Agents Chemother. 2019 Sep 23;63(10). doi: 10.1128/AAC.01006-19. Print 2019 Oct.
Mechanisms of magnesium homeostasis in 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/Co transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating and nonreplicating conditions 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 homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.
镁稳态的机制在 中理解得很差。在这里，我们描述了嘧啶三酮酰胺支架的特性，该支架通过直接与 CorA Mg/Co 转运体结合来破坏病原体中的镁稳态。CorA 的预测调节孔对镁离子响应的域中的突变赋予了对该支架的抗性。嘧啶三酮酰胺在主动复制和非复制条件下对病原体均具有杀菌作用，并且在巨噬细胞感染期间对该生物体有效。然而，该化合物在感染的小鼠中没有疗效，可能是由于暴露有限。我们的结果表明，CorA 抑制镁稳态是结核病药物发现的一个有吸引力的目标，并鼓励鉴定出改进的 CorA 抑制剂。
