Wall Teichoic Acid Biosynthesis: A New Target for Therapeutic Intervention?

壁磷壁酸生物合成：治疗干预的新目标？

• 批准号: 7264712
• 负责人: Suzanne Walker
• 金额: $ 42.28万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264712
• 关键词: Address; Anabolism; Animal Model; Anti-Infective Agents; Antibiotic Resistance; Antimicrobial susceptibility; Bacteria; Bacterial Infections; Behavior; Biochemistry; Biological Assay; Biological Models; Buffers; Cell Wall; Cell surface; Chemicals; Communities; Condition; Enterococcus faecalis; Enzymatic Biochemistry; Enzymes; Foundations; Genes; Genetic; Goals; Gram-Positive Bacteria; In Vitro; Individual; Infection; Intervention; Ions; Kinetics; Length; Listeria monocytogenes; Metabolic Pathway; Metals; Methods; Microbial Physiology; Molecular; Monitor; NADP; Organism; Orthologous Gene; Pathogenesis; Pathway interactions; Play; Polymers; Production; Protein Overexpression; Public Health; Range; Reaction; Reporting; Research; Research Personnel; Resistance; Role; Screening procedure; Staphylococcus aureus; Staphylococcus epidermidis; Streptococcus pneumoniae; Substrate Specificity; Surface; Teichoic Acids; Testing; Therapeutic; Therapeutic Intervention; Vancomycin-resistant S. aureus; Virulence; Virulence Factors; Virulent; Walkers; Work; analog; antimicrobial; base; chemotherapy; cytidine diphosphate ribitol; high throughput screening; inhibitor/antagonist; inorganic phosphate; interest; microorganism; pathogen; pathogenic bacteria; polyglycerol; polyribitol phosphate; programs; reconstitution; research study; ribitol-5-phosphate; ribulose; tool

DESCRIPTION (provided by applicant): Antibiotic resistance poses a significant threat to public health. The emergence of several vancomycin-resistant Staphylococcus aureus strains in recent years is particularly frightening because S. aureus is a highly virulent pathogen. There is a pressing need for new strategies to treat resistant Gram positive infections. The long term goal of the proposed research is to evaluate a largely unexplored metabolic pathway as a target for antimicrobial chemotherapy. This pathway, found in many pathogenic Gram positive bacteria, involves the biosynthesis of wall teichoic acids (WTAs). Wall teichoic acids are surface-associated anionic polymers. In some organisms these polymers are essential for survival; in S. aureus, they function as virulence factors that play a critical role in the establishment and spread of infection. Therefore, strategies to disrupt wall teichoic acid biosynthesis may have therapeutic utility. The specific aims of the research include: I) Elucidating the enzymology of key WTA biosynthetic enzymes from B. subtilis, the major Gram positive model organism. Chemical methods, approaches, and tools will be developed to study TagA, TagB, and TagF, three enzymes involved in WTA biosynthesis in B. subtilis 168. Unusual features of these enzymes will be explored. II) Characterizing the pathway for WTA biosynthesis in S. aureus using a combination of genetics and in vitro biochemistry. The approaches developed to study the 6. subtilis enzymes will be applied to characterize the S. aureus enzymes. Unresolved questions about WTA biosynthesis in S. aureus will be addressed. III) Establishing a multi-target high throughput screen for wall teichoic acid biosynthesis. An in vitro screen for several successive enzymes involved in WTA biosynthesis will be established and implemented, and the hits will be evaluated against B. subtilis and S. aureus targets. The experiments outlined in this proposal will lay the groundwork for evaluating wall teichoic acid biosynthesis as a target for antimicrobial chemotherapy and will provide fundamental information about the WTA pathway in S. aureus and about some of the more interesting WTA enzymes.

描述（由申请人提供）：抗生素耐药性对公众健康构成重大威胁。近年来出现的几种万古霉素耐药金黄色葡萄球菌菌株尤其令人恐惧，因为S。金黄色葡萄球菌是一种高毒性病原体。迫切需要新的策略来治疗耐药性革兰氏阳性感染。拟议研究的长期目标是评估一个基本上未探索的代谢途径作为抗菌化疗的靶点。在许多致病性革兰氏阳性细菌中发现的该途径涉及壁磷壁酸（WTA）的生物合成。壁磷壁酸是表面缔合的阴离子聚合物。在某些生物体中，这些聚合物是生存所必需的;在金黄色葡萄球菌中，它们作为毒力因子发挥作用，在感染的建立和传播中发挥关键作用。因此，破坏壁磷壁酸生物合成的策略可能具有治疗效用。本研究的具体目标包括：1）阐明B中WTA生物合成关键酶的酶学性质。枯草杆菌，主要的革兰氏阳性模式生物。将开发化学方法、途径和工具来研究B中涉及WTA生物合成的三种酶TagA、TagB和TagF。subtilis 168.这些酶的不寻常的功能将被探索。II）表征S.金黄色葡萄球菌使用遗传学和体外生物化学的组合。该方法开发的研究6。枯草杆菌酶将被应用于表征S.金黄色葡萄球菌酶关于S.将处理金黄色葡萄球菌。III）建立壁磷壁酸生物合成的多靶点高通量筛选。将建立并实施参与WTA生物合成的几种连续酶的体外筛选，并将针对B评价命中。subtilis和S.金黄色葡萄球菌目标。在这个提议中概述的实验将为评估壁磷壁酸生物合成作为抗微生物化疗的靶点奠定基础，并将提供关于S.金黄色葡萄球菌和一些更有趣的WTA酶。