Targeting DXP synthase in bacterial metabolism

靶向细菌代谢中的 DXP 合酶

• 批准号: 10372207
• 负责人: Caren L. Freel Meyers
• 金额: $ 57.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372207
• 关键词: Address; Anabolism; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Bacteria; Cell physiology; Centers for Disease Control and Prevention (U.S.); Clinical; Combined Modality Therapy; Development; Diphosphates; Drug Kinetics; Drug Targeting; Drug resistance; Environment; Enzymatic Biochemistry; Enzymes; Goals; Growth; Human; Immune response; Infection; Learning; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Nutrient; Nutritional; Outcome; Pathogenicity; Pathway interactions; Permeability; Positioning Attribute; Predisposition; Prevalence; Prodrugs; Public Health; Pyridoxal Phosphate; Reaction; Research; Resistance; Role; Serine; Stress; Structure; Testing; Thiamine; Urinary tract; Urinary tract infection; Uropathogen; Vitamins; Work; analog; antibiotic resistant infections; antimicrobial; ascending urinary tract infection; bacterial metabolism; base; combat; design; efficacy evaluation; efficacy study; efficacy testing; feeding; in vivo; inhibitor; inorganic phosphate; isoprenoid; mutant; pathogen; pathogenic bacteria; prevent; synergism; targeted agent; targeted treatment; uptake; xylulose-5-phosphate

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.

迫切需要开发新的抗菌素策略，以对抗临床病原菌中不断增加的耐药性。目前的抗生素作用于一系列有限的细胞过程，新抑制剂的发现速度正在迅速下降。随着有用抗生素武器库的减少，必须探索其他基本的细胞过程作为抗菌目标。在感染期间，细菌病原体通过重塑新陈代谢来促进生长，对宿主微环境的变化做出快速反应。这些“代谢适应”对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一个有前途的目标空间。1-脱氧-D-木糖-5-磷酸合成酶(DXPs)位于代谢支点，提供必需的维生素和异戊二烯类化合物，在细菌感染期间的代谢适应中发挥着关键作用，因此是一个潜在的靶点。我们揭示了DXPs结构和机制的几个独特特征，这些特征和机制指导了选择性抑制剂的开发，这些抑制剂通过涉及DXPs抑制的机制发挥抗菌活性。我们的研究将验证抑制DXPs将严重阻碍病原体在宿主中的代谢适应的假设，并采取下一步针对临床病原体的DXPs的抗菌策略。