Novel Inhibitors of DNA Ligase LigA by Substrate-Assisted Tethered Inhibition

通过底物辅助束缚抑制的 DNA 连接酶 LigA 新型抑制剂

基本信息

  • 批准号:
    9089917
  • 负责人:
  • 金额:
    $ 21.27万
  • 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:
    2015-07-01 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Novel therapeutics are needed to treat infections caused by antibiotic-resistant Gram-negative ESKAPE pathogens. DNA Ligase LigA is a validated target for antibacterial discovery, however the translation of LigA competitive inhibitor has been hindered by the rapid emergence of resistance mutations. We will use an innovative substrate-assisted tethered inhibition strategy to develop potent inhibitors of LigA that form a covalent adduct with enzyme-intermediate(s) on the reaction pathway. These inhibitors will thus be uncompetitive with NAD+, circumventing a major mechanism of resistance. We will also seek to identify inhibitors that have long residence times on the enzyme. This will result in increased target suppression at low drug concentration thereby reducing the emergence of resistance while simultaneously improving the therapeutic window of the compounds. In the R21 phase of the proposal, we will synthesize a focused library of oxaboroles (~100-150) guided by our initial modeling and determine the ability of these compounds to inhibit the LigA from K. pneumonia, A. baumannii P. aeruginosa, and E. coli. We will determine MICs against wild-type and efflux-pump mutants of each pathogen (Aim 1). We will develop structure-activity relationships for LigA inhibition using enzyme kinetics, X-ray crystallography and computational approaches (Aim 2) to inform additional compound synthesis. The objective of this aim will be to identify non/uncompetitive inhibitors with IC50 < 1 µM Kd < 0.1 µM (for E-AMP binding) and MIC < 8 µg/ml against efflux-pump strains. In the R33 phase we will focus our efforts on pathogen(s) that demonstrated the greatest sensitivity to the LigA inhibitors in the R21 phase and synthesize additional compounds with improved antibacterial activity against wild-type strain(s). The objective of the R33 phase is to deliver compound(s) with in vivo efficacy (= 1 log CFU decrease) and suitable properties for further optimization and preclinical development. Activities will include improving microbiological activity against wild-type strains, assessment of resistance frequency and in vitro and in vivo DMPK.


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)

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PETER J TONGE其他文献

PETER J TONGE的其他文献

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{{ truncateString('PETER J TONGE', 18)}}的其他基金

Mechanism of Slow Onset Enzyme Inhibition and Translation to Time-Dependent Drug Activity
缓慢起效的酶抑制机制及其转化为时间依赖性药物活性
  • 批准号:
    10623704
  • 财政年份:
    2023
  • 资助金额:
    $ 21.27万
  • 项目类别:
A PET Diagnostic for Imaging Bacterial Infection
细菌感染成像 PET 诊断
  • 批准号:
    10006663
  • 财政年份:
    2020
  • 资助金额:
    $ 21.27万
  • 项目类别:
Evaluation of a Novel Infection PET Diagnostic
新型感染 PET 诊断的评估
  • 批准号:
    10020585
  • 财政年份:
    2019
  • 资助金额:
    $ 21.27万
  • 项目类别:
Novel PET Radiotracers for Imaging Infection
用于感染成像的新型 PET 放射性示踪剂
  • 批准号:
    10165712
  • 财政年份:
    2018
  • 资助金额:
    $ 21.27万
  • 项目类别:
Novel PET Radiotracers for Imaging Infection
用于感染成像的新型 PET 放射性示踪剂
  • 批准号:
    9768480
  • 财政年份:
    2018
  • 资助金额:
    $ 21.27万
  • 项目类别:
Novel Inhibitors of DNA Ligase LigA by Substrate-Assisted Tethered Inhibition
通过底物辅助束缚抑制的 DNA 连接酶 LigA 新型抑制剂
  • 批准号:
    8956176
  • 财政年份:
    2015
  • 资助金额:
    $ 21.27万
  • 项目类别:
Mechanism of Slow Onset Enzyme Inhibition and Drug Target Residence Time
缓慢起效的酶抑制机制和药物靶标停留时间
  • 批准号:
    8545198
  • 财政年份:
    2012
  • 资助金额:
    $ 21.27万
  • 项目类别:
Mechanism of Slow Onset Enzyme Inhibition and Drug Target Residence Time
缓慢起效的酶抑制机制和药物靶标停留时间
  • 批准号:
    8918683
  • 财政年份:
    2012
  • 资助金额:
    $ 21.27万
  • 项目类别:
Mechanism of Slow Onset Enzyme Inhibition and Drug Target Residence Time
缓慢起效的酶抑制机制和药物靶标停留时间
  • 批准号:
    8727068
  • 财政年份:
    2012
  • 资助金额:
    $ 21.27万
  • 项目类别:
Mechanism of Slow Onset Enzyme Inhibition and Translation to Time-Dependent Drug Activity
缓慢起效的酶抑制机制及其转化为时间依赖性药物活性
  • 批准号:
    9896835
  • 财政年份:
    2012
  • 资助金额:
    $ 21.27万
  • 项目类别:

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