Molecular Targets in Peptidoglycan Synthesis

肽聚糖合成中的分子靶标

基本信息

项目摘要

Beta-lactam antibiotics, which target the essential transpeptidases (penicillin-binding proteins or PBPs) that cross-link peptidoglycan strands, are important drugs in the treatment of bacterial diseases. Unfortunately, the emergence of antibiotic-resistant pathogenic bacteria is a growing problem and threatens to make these and other antibiotics obsolete. Penicillin and tetracycline are no longer used to treat gonococcal infections due to the emergence of resistant strains of N. gonorrhoeae. Moreover, resistance to fluoroquinolones and third-generation cephalosporins, the two classes of antibiotics current recommended in the treatment of gonorrhea, is increasing. Clearly there is an urgent need to develop new antimicrobials directed both against well-known molecular targets, such as PBPs, but also against novel targets such as transglycosylases (TGases), which catalyze the polymerization of glycan stands, and autolysins, which break down peptidoglycan during biosynthesis. Development of new antibiotics, however, has been hindered by a dearth of mechanistic information for these enzymes. In this proposal we describe genetic, biochemical and structural studies of three classes of enzyme involved in peptidoglycan metabolism in N. gonorrhoeae. Each has been selected to address one or more of the following aims: (a) to understand the biology of peptidoglycan synthesis, (b) to explore their interactions with antibiotics, (c) to elucidate the molecular basis for antibiotic resistance and (d) to examine their potential as targets for drug development. The molecular basis for antibiotic resistance will be investigated by structural and biochemical studies of a unique variant of PBP 2 from strains of N. gonorrhoeae with intermediate-level resistance to ceftriaxone. The role of the lytic TGase MltA as part of a multienzyme complex involved in cell division will be investigated by genetic studies. The suitability of the amidase AmiC as a novel target for antimicrobials will be examined both genetically and by solving its crystal structure. Finally, the crystal structure of a TGase domain will reveal the catalytic mechanism of these enzymes and pave the way for drug design. Together, these studies will provide insight into the functional roles of these proteins in peptidoglycan metabolism but also the essential molecular information needed to bolster the current repertoire of antimicrobials directed against pathogenic bacteria. The sexually transmitted disease gonorrhea is a growing public-health problem due to the emergence of strains harboring resistance to antibiotics such as penicillin. The development of new treatments for gonococcal disease requires detailed, three-dimensional pictures of essential proteins in these bacteria for use in drug discovery. This project will use X-ray crystallography to provide such information for a number of key proteins in N. gonorrhoeae that are involved in cell wall synthesis.
β-内酰胺抗生素靶向交联肽聚糖链的必需转肽酶(青霉素结合蛋白或PBPs),是治疗细菌性疾病的重要药物。不幸的是,抗药性病原菌的出现是一个日益严重的问题,并威胁到这些和其他抗生素的过时。青霉素和四环素不再用于治疗淋球菌感染,由于耐药菌株的出现。淋病此外,对氟喹诺酮类和第三代头孢菌素(目前推荐用于治疗淋病的两类抗生素)的耐药性正在增加。显然,迫切需要开发既针对众所周知的分子靶标(如PBP),又针对新靶标(如催化聚糖链聚合的转糖基酶(TGases)和在生物合成期间分解肽聚糖的自溶素)的新抗微生物剂。然而,由于缺乏这些酶的机制信息,新抗生素的开发受到阻碍。在这篇论文中,我们描述了N.淋病每一个都被选择来解决以下一个或多个目标:(a)了解肽聚糖合成的生物学,(B)探索它们与抗生素的相互作用,(c)阐明抗生素耐药性的分子基础,(d)检查它们作为药物开发靶点的潜力。抗生素耐药性的分子基础将通过对来自N.对头孢曲松有中等耐药性的淋病。作为参与细胞分裂的多酶复合物的一部分,裂解性TGase MltA的作用将通过遗传研究进行研究。酰胺酶AmiC作为抗微生物剂的新靶点的适用性将通过遗传学和解决其晶体结构来检查。最后,TGase结构域的晶体结构将揭示这些酶的催化机制,并为药物设计铺平道路。总之,这些研究将深入了解这些蛋白质在肽聚糖代谢中的功能作用,以及支持目前针对病原菌的抗菌药物所需的基本分子信息。 由于出现了对青霉素等抗生素具有耐药性的菌株,性传播疾病淋病是一个日益严重的公共卫生问题。开发淋球菌疾病的新疗法需要这些细菌中必需蛋白质的详细三维图像,以用于药物发现。该项目将使用X射线晶体学来提供N.参与细胞壁合成的淋病。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Christopher Davies其他文献

Christopher Davies的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Christopher Davies', 18)}}的其他基金

PlzA, cyclic-di-GMP and the enzootic cycle for Lyme disease
PlzA、环二 GMP 和莱姆病的地方性循环
  • 批准号:
    10608622
  • 财政年份:
    2022
  • 资助金额:
    $ 30.35万
  • 项目类别:
Molecular mechanism of cephalosporin resistance of N. gonorrhoeae conferred by mutated PBP2
PBP2突变导致淋病奈瑟菌头孢菌素耐药的分子机制
  • 批准号:
    10467153
  • 财政年份:
    2022
  • 资助金额:
    $ 30.35万
  • 项目类别:
Molecular mechanism of cephalosporin resistance of N. gonorrhoeae conferred by mutated PBP2
PBP2突变导致淋病奈瑟菌头孢菌素耐药的分子机制
  • 批准号:
    10589915
  • 财政年份:
    2022
  • 资助金额:
    $ 30.35万
  • 项目类别:
Crystallization robotics to support X-ray crystallography at MUSC
结晶机器人为 MUSC 的 X 射线晶体学提供支持
  • 批准号:
    8052518
  • 财政年份:
    2011
  • 资助金额:
    $ 30.35万
  • 项目类别:
SC COBRE: PROTEIN SCIENCE CORE
SC COBRE:蛋白质科学核心
  • 批准号:
    8168045
  • 财政年份:
    2010
  • 资助金额:
    $ 30.35万
  • 项目类别:
SC COBRE: PROTEIN SCIENCE CORE
SC COBRE:蛋白质科学核心
  • 批准号:
    7959964
  • 财政年份:
    2009
  • 资助金额:
    $ 30.35万
  • 项目类别:
Molecular Targets in Peptidoglycan Synthesis
肽聚糖合成中的分子靶标
  • 批准号:
    7929954
  • 财政年份:
    2009
  • 资助金额:
    $ 30.35万
  • 项目类别:
SC COBRE: PROTEIN SCIENCE CORE
SC COBRE:蛋白质科学核心
  • 批准号:
    7720845
  • 财政年份:
    2008
  • 资助金额:
    $ 30.35万
  • 项目类别:
Molecular Targets in Peptidoglycan Synthesis
肽聚糖合成中的分子靶标
  • 批准号:
    6558096
  • 财政年份:
    2003
  • 资助金额:
    $ 30.35万
  • 项目类别:
Molecular Targets in Peptidoglycan Synthesis
肽聚糖合成中的分子靶标
  • 批准号:
    7365152
  • 财政年份:
    2003
  • 资助金额:
    $ 30.35万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 30.35万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了