1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) catalyzes the second step of the non-mevalonate (or MEP) pathway that functions in several organisms and plants for the synthesis of isoprenoids. DXR is essential for the survival of multiple pathogenic bacteria/parasites, including those that cause tuberculosis and malaria in humans. DXR function is inhibited by fosmidomycin (1), a natural product, which forms a chelate with the active site divalent metal (Mg²⁺/Mn²⁺) through its hydroxamate metal-binding group (MBG). Most of the potent DXR inhibitors are structurally similar to 1 and retain hydroxamate despite the unfavourable pharmacokinetic and toxicity profile of the latter. We provide our perspective on the lack of non-hydroxamate DXR inhibitors. We also highlight the fundamental flaws in the design of MBG in these molecules, primarily responsible for their failure to inhibit DXR. We also suggest that for designing next-generation non-hydroxamate DXR inhibitors, approaches followed for other metalloenzymes targets may be exploited.

1-脱氧-D-木酮糖-5-磷酸还原异构酶（DXR）催化非甲羟戊酸（或MEP）途径的第二步，该途径在多种生物和植物中发挥作用，合成类异戊二烯。DXR对于多种致病细菌/寄生虫（包括在人类中引起结核病和疟疾的细菌）的生存至关重要。fosmidomycin（1）是一种天然产物，它通过异羟肟酸金属结合基团（MBG）与活性部位的二价金属（Mg ²⁺ / Mn ²⁺）形成螯合物，从而抑制DXR功能。大多数有效的DXR抑制剂在结构上与1和保留异羟肟酸酯，尽管后者的药代动力学和毒性不利。我们对缺乏非异羟肟酸酯DXR抑制剂提供了看法。我们还强调了这些分子MBG设计中的基本缺陷，这主要是由于它们不能抑制DXR。我们还建议，在设计下一代非异羟肟酸酯DXR抑制剂时，可采用针对其他金属酶靶标的方法。