Targeting DXP synthase in bacterial metabolism

迫切需要开发新的抗菌策略来对抗临床病原体中日益增加的耐药性。目前的抗生素作用于有限的细胞过程，新抑制剂的发现率正在迅速下降。随着有用抗生素的减少，必须探索其他基本细胞过程作为抗菌靶点。在感染期间，细菌病原体通过重塑代谢以促进生长来迅速响应宿主微环境的变化。这些“代谢适应”对于病原体在体内的存活和致病性至关重要，因此是抗生素开发的有希望的靶向空间。1-脱氧-D-木酮糖-5-磷酸合酶（1-deoxy-D-xylulose 5-phosphate synthase，DXPS）位于代谢分支点，提供必需的维生素和类异戊二烯，是细菌感染过程中代谢适应的重要参与者，因此它是一个潜在的靶标。我们已经发现了DXPS结构和机制的几个独特的功能，指导了选择性抑制剂的发展，发挥抗菌活性的机制，涉及DXPS抑制。我们的研究将检验抑制DXPS将严重阻碍宿主中病原体代谢适应的假设，并采取下一步措施开发针对临床病原体中DXPS的抗菌策略。

There is an urgent need to develop new antimicrobial strategies to combat the increasing occurrence of drug resistance in clinical pathogens. Current antibiotics act on a limited set of cellular processes, and the rate of new inhibitor discovery is rapidly declining. With the diminishing arsenal of useful antibiotics, other essential cellular processes must be explored as antibacterial targets. During infection, bacterial pathogens rapidly respond to changes in the host microenvironment by remodeling metabolism to promote growth. These “metabolic adaptations” are crucial for pathogen survival and pathogenicity in vivo and are thus a promising target space for antibiotic development. Positioned at a metabolic branch point to supply essential vitamins and isoprenoids, 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) is poised to be a key player in bacterial metabolic adaptation during infection, thus it is a potential target. We have uncovered several unique features of DXPS structure and mechanism that have guided the development of selective inhibitors that exert antibacterial activity by a mechanism involving DXPS inhibition. Our research will test the hypothesis that inhibition of DXPS will severely hinder pathogen metabolic adaptation in the host and take the next steps to develop antibacterial strategies targeting DXPS in clinical pathogens.