Targeting DXP synthase in bacterial metabolism

靶向细菌代谢中的 DXP 合酶

基本信息

批准号：
10576858
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
项目类别：
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/10576858
关键词：
Address Anabolism Anti-Bacterial Agents Antibiotics Antimicrobial Resistance Bacteria Cell physiology 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 combat design efficacy evaluation efficacy study efficacy testing feeding in vivo inhibitor inorganic phosphate isoprenoid mutant pathogen pathogenic bacteria prevent priority pathogen synergism targeted agent targeted treatment uptake xylulose-5-phosphate

项目摘要

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策略，以打击临床病原体中耐药性增加的增加。当前的抗生素对有限的细胞过程作用，新抑制剂发现的速率正在迅速下降。随着有用抗生素的武库减少，必须将其他必要的细胞过程作为抗菌靶标探索。在感染过程中，细菌病原体通过重塑代谢以促进生长而迅速响应宿主微环境的变化。这些“代谢适应性”对于体内的病原体存活和致病性至关重要，因此是抗生素发育的有希望的目标空间。 1-脱氧-D-氧基5-磷酸合酶（DXPS）位于代谢分支点以供应必需的维生素和类异on-，被中毒是在感染过程中细菌代谢适应的关键参与者，因此它是一个潜在的靶标。我们发现了DXPS结构和机制的几个独特特征，这些特征指导了通过所涉及的机制发挥抗菌活性的选择性抑制剂的发展。我们的研究将检验以下假设：DXP的抑制作用将严重阻碍宿主中的病原体代谢适应，并采取下一步制定针对临床病原体DXP的抗菌策略。