Structural and Functional Characterization of RNA polymerase and its Regulators from Mycobacterium tuberculosis and Clostridioides difficile

结核分枝杆菌和艰难梭菌 RNA 聚合酶及其调节剂的结构和功能表征

基本信息

  • 批准号:
    10586042
  • 负责人:
  • 金额:
    $ 33.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-04-01 至 2024-05-31
  • 项目状态:
    已结题

项目摘要

Project Summary Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), continues to pose a major health problem. The Center for Disease Control estimates that approximately 1/3 to 1/4 of the world’s population is latently infected. RNA polymerase (RNAP), the enzyme responsible for all transcription in bacteria, is the target for the Rifamycin (Rif) class of antibiotics, a first line therapeutic treatment for TB. RNAP is thus a proven and attractive target for the development of new drugs. This highlights the importance of our recent structural and functional characterization of Mtb RNAP and the roles of two essential transcription factors required for full transcriptional activity. The previous grant enabled us to provide a 2.8 Å resolution crystal structure of an RNAP transcription initiation complex (TIC) from M. smegmatis and more recently cryo-EM structures of Mtb transcription complexes. In this proposal, cryo-EM will be used to examine RNAP complexes as a starting point to elucidate the mechanisms of a family of relatively uncharacterized transcription factors, the WhiB factors. The WhiB factors are only found in Actinobacteria and have roles in Mtb that include essentiality for growth and division, and responses to host induced stresses including antibiotic tolerance, nitric oxide, macrophage invasion and reactive oxygen species. We will use a multidisciplinary approach that includes structural, biochemical, genomic and in vivo experiments (in collaboration with J. Rock) to understand the roles and mechanism of this important, but relatively uncharacterized family of transcription factors. The results from the aims here have the potential to not only elucidate the mechanism and biology of these factors, but also provide a platform for new targets for clade-specific antibiotic development and serve to guide us on how to increase the efficacy of the current repertoire of antibiotics. The results from the previous funding period have led to high resolution structures of Mycobacteria RNAP (by cryo-EM and crystallography), and provided the opportunity to characterize how Rif and Rif derivatives that inhibit Rif resistant (RifR) bacteria inhibit Mycobacteria RNAP. Here we propose to continue this line of research with structurally uncharacterized Rif derivatives, provided by S. Brady, that inhibit additional RifR Mtb RNAPs. Clostrioides difficile (Cdiff), a Gram-positive, sporulating, anaerobic bacterium, is an opportunistic pathogen which is deadly to compromised hosts. Fidaxomicin (Fdx), the only other FDA approved antibiotic which targets RNAP, is a powerful treatment for Cdiff infection. Our recent work established that Fdx can inhibit Mtb RNAP potently, but that potency is dependent on the Actinobacteria-specific transcription factor RpbA, which is absent in Cdiff. Here we propose to extend our expertise in biochemical and structural studies of bacterial RNAPs to include the previously uncharacterized clade of Firmicutes to which Cdiff belongs. The results here will elucidate the structural and biochemical basis for Fdx potency as well as provide a structural and biochemical basis for exploiting Cdiff RNAP for drug development and optimization.
项目总结

项目成果

期刊论文数量(24)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The essential M. tuberculosis Clp protease is functionally asymmetric in vivo.
  • DOI:
    10.1126/sciadv.abn7943
  • 发表时间:
    2022-05-06
  • 期刊:
  • 影响因子:
    13.6
  • 作者:
  • 通讯作者:
CarD uses a minor groove wedge mechanism to stabilize the RNA polymerase open promoter complex.
  • DOI:
    10.7554/elife.08505
  • 发表时间:
    2015-09-08
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Bae B;Chen J;Davis E;Leon K;Darst SA;Campbell EA
  • 通讯作者:
    Campbell EA
CoV-er all the bases: Structural perspectives of SARS-CoV-2 RNA synthesis.
  • DOI:
    10.1016/bs.enz.2021.06.004
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Malone B;Campbell EA;Darst SA
  • 通讯作者:
    Darst SA
Structures and functions of coronavirus replication-transcription complexes and their relevance for SARS-CoV-2 drug design.
  • DOI:
    10.1038/s41580-021-00432-z
  • 发表时间:
    2022-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Malone B;Urakova N;Snijder EJ;Campbell EA
  • 通讯作者:
    Campbell EA
Diverse and unified mechanisms of transcription initiation in bacteria.
细菌中转录起始的多样化且统一的机制。
  • DOI:
    10.1038/s41579-020-00450-2
  • 发表时间:
    2021-03
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Chen J;Boyaci H;Campbell EA
  • 通讯作者:
    Campbell EA
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ELIZABETH A CAMPBELL其他文献

ELIZABETH A CAMPBELL的其他文献

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{{ truncateString('ELIZABETH A CAMPBELL', 18)}}的其他基金

Structure, function, and inhibition of the SARS-CoV-2 replication-transcription complex
SARS-CoV-2 复制转录复合物的结构、功能和抑制
  • 批准号:
    10238209
  • 财政年份:
    2021
  • 资助金额:
    $ 33.9万
  • 项目类别:
Structure, function, and inhibition of the SARS-CoV-2 replication-transcription complex
SARS-CoV-2 复制转录复合物的结构、功能和抑制
  • 批准号:
    10463632
  • 财政年份:
    2021
  • 资助金额:
    $ 33.9万
  • 项目类别:
Structure, function, and inhibition of the SARS-CoV-2 replication-transcription complex
SARS-CoV-2 复制转录复合物的结构、功能和抑制
  • 批准号:
    10669076
  • 财政年份:
    2021
  • 资助金额:
    $ 33.9万
  • 项目类别:
Structural and Functional Characterization of RNA polymerase and its Regulators from Mycobacterium tuberculosis and Clostridioides difficile
结核分枝杆菌和艰难梭菌 RNA 聚合酶及其调节剂的结构和功能表征
  • 批准号:
    10581925
  • 财政年份:
    2015
  • 资助金额:
    $ 33.9万
  • 项目类别:
Structural and Functional Characterization of RNA polymerase and its Regulators from Mycobacterium tuberculosis and Clostridioides difficile
结核分枝杆菌和艰难梭菌 RNA 聚合酶及其调节剂的结构和功能表征
  • 批准号:
    10370352
  • 财政年份:
    2015
  • 资助金额:
    $ 33.9万
  • 项目类别:
Structural and Functional Characterization of RNA polymerase and its Regulators from Mycobacterium tuberculosis and Clostridioides difficile
结核分枝杆菌和艰难梭菌 RNA 聚合酶及其调节剂的结构和功能表征
  • 批准号:
    10388936
  • 财政年份:
    2015
  • 资助金额:
    $ 33.9万
  • 项目类别:
Structure/function analyses of essential mycobacterial transcription regulators
分枝杆菌必需转录调节因子的结构/功能分析
  • 批准号:
    9041636
  • 财政年份:
    2015
  • 资助金额:
    $ 33.9万
  • 项目类别:
Structure/function analyses of essential mycobacterial transcription regulators
分枝杆菌必需转录调节因子的结构/功能分析
  • 批准号:
    8861934
  • 财政年份:
    2015
  • 资助金额:
    $ 33.9万
  • 项目类别:
STRUCTURE OF THE BACTERIAL RNA POLYMERASE PROMOTER
细菌RNA聚合酶启动子的结构
  • 批准号:
    6975789
  • 财政年份:
    2004
  • 资助金额:
    $ 33.9万
  • 项目类别:
STRUCTURAL STUDIES OF RNA POLYMERASE COMPLEXES
RNA聚合酶复合物的结构研究
  • 批准号:
    6135045
  • 财政年份:
    2000
  • 资助金额:
    $ 33.9万
  • 项目类别:

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合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
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