• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

InhA的一种不依赖辅因子的抑制剂的发现。

Discovery of a cofactor-independent inhibitor of InhA.

作者信息

Xia Yi, Zhou Yasheen, Carter David S, McNeil Matthew B, Choi Wai, Halladay Jason, Berry Pamela W, Mao Weimin, Hernandez Vincent, O'Malley Theresa, Korkegian Aaron, Sunde Bjorn, Flint Lindsay, Woolhiser Lisa K, Scherman Michael S, Gruppo Veronica, Hastings Courtney, Robertson Gregory T, Ioerger Thomas R, Sacchettini Jim, Tonge Peter J, Lenaerts Anne J, Parish Tanya, Alley Mrk

机构信息

Anacor Pharmaceuticals, Palo Alto, CA, USA.

TB Discovery Research, Infectious Disease Research Institute, Seattle, WA, USA.

出版信息

Life Sci Alliance. 2018 Jun 1;1(3):e201800025. doi: 10.26508/lsa.201800025. eCollection 2018 Jun.

DOI:10.26508/lsa.201800025
PMID:30456352
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6238539/
Abstract

New antitubercular agents are needed to combat the spread of multidrug- and extensively drug-resistant strains of . The frontline antitubercular drug isoniazid (INH) targets the mycobacterial enoyl-ACP reductase, InhA. Resistance to INH is predominantly through mutations affecting the prodrug-activating enzyme KatG. Here, we report the identification of the diazaborines as a new class of direct InhA inhibitors. The lead compound, AN12855, exhibited in vitro bactericidal activity against replicating bacteria and was active against several drug-resistant clinical isolates. Biophysical and structural investigations revealed that AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. AN12855 showed good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibited dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection that was comparable with INH. Combined, AN12855 is a promising candidate for the development of new antitubercular agents.

摘要

需要新型抗结核药物来对抗耐多药和广泛耐药结核菌株的传播。一线抗结核药物异烟肼（INH）作用于分枝杆菌烯酰-ACP还原酶InhA。对INH的耐药主要是通过影响前药激活酶KatG的突变产生。在此，我们报告了二氮杂硼烷类作为一类新型InhA直接抑制剂的鉴定。先导化合物AN12855对增殖期细菌表现出体外杀菌活性，并且对几种耐药临床分离株有活性。生物物理和结构研究表明，AN12855以不依赖辅因子的方式结合并抑制InhA的底物结合位点。静脉注射和口服给药后，AN12855均显示出良好的药物暴露，口服生物利用度为53%。口服给药时，AN12855在急性和慢性小鼠结核感染模型中均表现出剂量依赖性疗效，与INH相当。综合来看，AN12855是开发新型抗结核药物的一个有前景的候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/019cef29e0b3/LSA-2018-00025_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/9cfaa5e521ae/LSA-2018-00025_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/f953d6b86a94/LSA-2018-00025_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/26a85887a091/LSA-2018-00025_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/6c3b9f88b39a/LSA-2018-00025_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/019cef29e0b3/LSA-2018-00025_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/9cfaa5e521ae/LSA-2018-00025_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/f953d6b86a94/LSA-2018-00025_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/26a85887a091/LSA-2018-00025_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/6c3b9f88b39a/LSA-2018-00025_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e4/6238539/019cef29e0b3/LSA-2018-00025_FigS1.jpg

相似文献

1
Discovery of a cofactor-independent inhibitor of InhA.InhA的一种不依赖辅因子的抑制剂的发现。
Life Sci Alliance. 2018 Jun 1;1(3):e201800025. doi: 10.26508/lsa.201800025. eCollection 2018 Jun.
2
Recent Advances and Structural Features of Enoyl-ACP Reductase Inhibitors of Mycobacterium tuberculosis.结核分枝杆菌烯酰-ACP还原酶抑制剂的最新进展与结构特征
Arch Pharm (Weinheim). 2016 Nov;349(11):817-826. doi: 10.1002/ardp.201600186. Epub 2016 Oct 24.
3
The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance.异烟肼-NAD加合物是结核分枝杆菌烯酰还原酶InhA的一种缓慢、紧密结合的抑制剂：加合物亲和力与耐药性。
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):13881-6. doi: 10.1073/pnas.2235848100. Epub 2003 Nov 17.
4
Development of modern InhA inhibitors to combat drug resistant strains of Mycobacterium tuberculosis.开发现代InhA抑制剂以对抗结核分枝杆菌的耐药菌株。
Curr Top Med Chem. 2007;7(5):489-98. doi: 10.2174/156802607780059781.
5
Direct inhibitors of InhA are active against Mycobacterium tuberculosis.InhA的直接抑制剂对结核分枝杆菌具有活性。
Sci Transl Med. 2015 Jan 7;7(269):269ra3. doi: 10.1126/scitranslmed.3010597.
6
N-Benzyl-4-((heteroaryl)methyl)benzamides: A New Class of Direct NADH-Dependent 2-trans Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity.N-苄基-4-（（杂芳基）甲基）苯甲酰胺：一类新型的直接依赖烟酰胺腺嘌呤二核苷酸（NADH）的2-反式烯酰-酰基载体蛋白还原酶（InhA）抑制剂，具有抗结核活性。
ChemMedChem. 2016 Apr 5;11(7):687-701. doi: 10.1002/cmdc.201600020. Epub 2016 Mar 2.
7
Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA.编码文库技术作为发现和优化强效和选择性杀菌直接抑制剂的新型结核分枝杆菌 InhA 的来源。
J Med Chem. 2014 Feb 27;57(4):1276-88. doi: 10.1021/jm401326j. Epub 2014 Feb 5.
8
Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology.利用DNA编码文库技术发现辅因子特异性的结核分枝杆菌InhA杀菌抑制剂
Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):E7880-E7889. doi: 10.1073/pnas.1610978113. Epub 2016 Nov 18.
9
Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in ?IQG-607是否是一种具有明确分子靶点的潜在金属药物或前体金属药物？
Front Microbiol. 2018 May 1;9:880. doi: 10.3389/fmicb.2018.00880. eCollection 2018.
10
The mutations of katG and inhA genes of isoniazid-resistant Mycobacterium tuberculosis isolates in Taiwan.台湾地区异烟肼耐药结核分枝杆菌分离株 katG 和 inhA 基因突变。
J Microbiol Immunol Infect. 2015 Jun;48(3):249-55. doi: 10.1016/j.jmii.2013.08.018. Epub 2013 Nov 1.

引用本文的文献

1
Is Mycobacterial InhA a Suitable Target for Rational Drug Design?分枝杆菌InhA是合理药物设计的合适靶点吗？
ChemMedChem. 2025 Jul 1;20(13):e202500079. doi: 10.1002/cmdc.202500079. Epub 2025 Apr 29.
2
Experimental and theoretical studies on antituberculosis activity of different benzimidazole derivatives.不同苯并咪唑衍生物抗结核活性的实验与理论研究
Heliyon. 2025 Feb 12;11(4):e42674. doi: 10.1016/j.heliyon.2025.e42674. eCollection 2025 Feb 28.
3
Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis.

本文引用的文献

1
Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA.针对结核分枝杆菌InhA直接抑制剂NITD-916的耐药机制
Tuberculosis (Edinb). 2017 Dec;107:133-136. doi: 10.1016/j.tube.2017.09.003. Epub 2017 Sep 13.
2
Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors.评估过渡态去稳定化对唑类 InhA 抑制剂停留时间变化的贡献。
J Am Chem Soc. 2017 Mar 8;139(9):3417-3429. doi: 10.1021/jacs.6b11148. Epub 2017 Feb 22.
3
Comparative study of enzymatic activities of new KatG mutants from low- and high-level isoniazid-resistant clinical isolates of Mycobacterium tuberculosis.
全基因组 CRISPRi 筛选鉴定耐异烟肼结核分枝杆菌菌株中的可药物治疗的弱点。
Nat Commun. 2024 Nov 13;15(1):9791. doi: 10.1038/s41467-024-54072-w.
4
Contribution of direct InhA inhibitors to novel drug regimens in a mouse model of tuberculosis.直接 InhA 抑制剂在结核分枝杆菌感染小鼠模型中新药物方案中的作用。
Antimicrob Agents Chemother. 2024 Nov 6;68(11):e0035724. doi: 10.1128/aac.00357-24. Epub 2024 Sep 30.
5
: Pathogenesis and therapeutic targets.发病机制与治疗靶点。
MedComm (2020). 2023 Sep 4;4(5):e353. doi: 10.1002/mco2.353. eCollection 2023 Oct.
6
Evaluating the Impact of the Tyr158 p on the Mechanism and Inhibition of InhA, the Enoyl-ACP Reductase from .评估 Tyr158p 对 InhA（烯酰基辅酶 A 还原酶）的机制和抑制的影响，InhA 来自 。
Biochemistry. 2023 Jun 20;62(12):1943-1952. doi: 10.1021/acs.biochem.2c00606. Epub 2023 Jun 4.
7
The pathogenic mechanism of Mycobacterium tuberculosis: implication for new drug development.结核分枝杆菌的致病机制：对新药研发的启示
Mol Biomed. 2022 Dec 22;3(1):48. doi: 10.1186/s43556-022-00106-y.
8
How drug resistance has shaped anti-tubercular drug discovery.耐药性如何塑造抗结核药物的发现。
Front Cell Infect Microbiol. 2022 Sep 9;12:974101. doi: 10.3389/fcimb.2022.974101. eCollection 2022.
9
The Boron Advantage: The Evolution and Diversification of Boron's Applications in Medicinal Chemistry.硼的优势：硼在药物化学中的应用演变与多样化
Pharmaceuticals (Basel). 2022 Feb 22;15(3):264. doi: 10.3390/ph15030264.
10
Designing of a Chimeric Vaccine Using EIS (Rv2416c) Protein Against Mycobacterium tuberculosis H37Rv: an Immunoinformatics Approach.基于免疫信息学方法设计的针对结核分枝杆菌 H37Rv 的嵌合疫苗（EIS（Rv2416c）蛋白）。
Appl Biochem Biotechnol. 2022 Jan;194(1):187-214. doi: 10.1007/s12010-021-03760-0. Epub 2021 Nov 24.
来自结核分枝杆菌低水平和高水平异烟肼耐药临床分离株的新型KatG突变体酶活性的比较研究
Tuberculosis (Edinb). 2016 Sep;100:15-24. doi: 10.1016/j.tube.2016.06.002. Epub 2016 Jun 16.
4
Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.针对一个旧靶点的抗结核药物：GSK693作为一种有前景的InhA直接抑制剂。
EBioMedicine. 2016 Jun;8:291-301. doi: 10.1016/j.ebiom.2016.05.006. Epub 2016 May 8.
5
Genetic mutations associated with isoniazid resistance in Mycobacterium tuberculosis: a systematic review.结核分枝杆菌中与异烟肼耐药相关的基因突变：一项系统评价
PLoS One. 2015 Mar 23;10(3):e0119628. doi: 10.1371/journal.pone.0119628. eCollection 2015.
6
Direct inhibitors of InhA are active against Mycobacterium tuberculosis.InhA的直接抑制剂对结核分枝杆菌具有活性。
Sci Transl Med. 2015 Jan 7;7(269):269ra3. doi: 10.1126/scitranslmed.3010597.
7
Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA.吡啶霉素桥接烯酰还原酶 InhA 的 NADH 和底物结合口袋。
Nat Chem Biol. 2014 Feb;10(2):96-8. doi: 10.1038/nchembio.1405. Epub 2013 Dec 1.
8
Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis.结核分枝杆菌中新的药物靶点和耐药机制的鉴定。
PLoS One. 2013 Sep 23;8(9):e75245. doi: 10.1371/journal.pone.0075245. eCollection 2013.
9
A dual read-out assay to evaluate the potency of compounds active against Mycobacterium tuberculosis.一种双读出测定法，用于评估抗结核分枝杆菌化合物的效力。
PLoS One. 2013 Apr 4;8(4):e60531. doi: 10.1371/journal.pone.0060531. Print 2013.
10
Discovery of a novel class of boron-based antibacterials with activity against gram-negative bacteria.发现一类新型硼基抗菌药物，对革兰氏阴性菌具有活性。
Antimicrob Agents Chemother. 2013 Mar;57(3):1394-403. doi: 10.1128/AAC.02058-12. Epub 2013 Jan 7.