Novel aminoglycoside adjuvants and stand-alone agents to combat tuberculosis

新型氨基糖苷类佐剂和单独的抗结核药物

基本信息

批准号：
10188396
负责人：
Sylvie Garneau-Tsodikova
金额：
$ 54.8万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188396
关键词：
AIDS/HIV problem Acetyltransferase Adjuvant Adjuvant Therapy Aminoglycosides Anti-Bacterial Agents Antibiotics Antitubercular Agents Area Bacteria Biochemical Biological Biological Assay Cells Cessation of life Chemicals Combined Modality Therapy Complex Consultations Coupled Crystallization Development Drug resistance Drug resistance in tuberculosis Epidemic Evaluation Exhibits Extreme drug resistant tuberculosis Funding Future Genotype Genus Mycobacterium Human In Vitro Infection Kanamycin Kanamycin A Knock-out Laboratories Lead Measurement Mediating Modeling Multidrug-Resistant Tuberculosis Mutation Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv Pathogenicity Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Property Reporting Resistance Resort Safety Solubility Structure Testing Therapeutic Toxic effect Tuberculosis Up-Regulation analog clinical development combat cytotoxicity design drug-sensitive experience extensive drug resistance genome sequencing infection burden inhibitor/antagonist innovation interest macrophage mouse model mutant novel novel strategies pre-clinical preclinical development preclinical study prevent promoter research clinical testing resistance mechanism scaffold structural biology success synergism

项目摘要

ABSTRACT Tuberculosis (TB) is the deadliest global infection (1.4 million deaths in 2015), having recently surpassed HIV/AIDS. ~250,000 of these deaths were from multidrug-resistant (MDR) TB, with only ~50% success in treatment of MDR-TB. Unless new strategies to combat or prevent emergence of drug-resistant TB are found, the global spread of MDR-TB will be an epidemic of epic proportions. Kanamycin A (KAN) is an antibiotic of last resort used to treat MDR-TB. Resistance to KAN signifies extensively drug-resistant (XDR) TB, which is nearly incurable. One-third of KAN-resistant TB is caused by upregulation of the acetyltransferase Eis in Mycobacterium tuberculosis (Mtb), caused by mutations in the eis promoter. We investigated the mechanism of Eis and discovered and validated several Eis inhibitor scaffolds in the previous funding period. In Aims 1 and 2 of this application, we propose to develop a novel strategy to combat and forestall KAN resistance in TB. These Aims are focused on the preclinical development of these Eis inhibitors for their ultimate use as a combination therapy with KAN against MDR-TB. In Aim 3, we propose to determine the mechanism(s) of the anti-Mtb activity of novel compounds that were discovered to inhibit Eis and potently inhibit Mtb bacteria without KAN, ultimately to develop them as therapeutics against both drug-resistant and drug-resistant TB.

抽象的结核病 (TB) 是全球最致命的感染（2015 年有 140 万人死亡），最近已超过艾滋病毒/艾滋病。其中约 250,000 人死于耐多药 (MDR) 结核病，其中只有约 50% 的成功率耐多药结核病的治疗。除非有新的策略来对抗或预防耐药结核病的出现研究发现，耐多药结核病将在全球范围内蔓延，成为史无前例的流行病。卡那霉素 A (KAN) 是一种用于治疗耐多药结核病的最后手段抗生素。对 KAN 的耐药性意味着广泛耐药 (XDR) 结核病，几乎无法治愈。三分之一的 KAN 耐药结核病是由 KAN 的上调引起的结核分枝杆菌 (Mtb) 中的乙酰转移酶 Eis，由 eis 启动子突变引起。我们研究了 Eis 的机制，发现并验证了几种 Eis 抑制剂支架之前的资助期。在本申请的目标 1 和 2 中，我们建议开发一种新颖的策略对抗和预防结核病中的 KAN 耐药性。这些目标侧重于临床前开发这些 Eis 抑制剂的最终用途是与 KAN 联合治疗耐多药结核病。在目标 3 中，我们建议确定新化合物的抗 Mtb 活性机制，这些化合物是发现无需 KAN 即可抑制 Eis 并有效抑制 Mtb 细菌，最终将其开发为针对耐药结核病和耐药结核病的治疗方法。

项目成果

期刊论文数量（55）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.

DOI：
10.1021/acs.biochem.2c00658
发表时间：
2023-01
期刊：
Biochemistry
影响因子：
2.9
作者：
A. Pang;Keith D. Green;A. Punetha;Nishad Thamban Chandrika;Kaitlind C Howard;S. Garneau‐Tsodikova;O. Tsodikov
通讯作者：
A. Pang;Keith D. Green;A. Punetha;Nishad Thamban Chandrika;Kaitlind C Howard;S. Garneau‐Tsodikova;O. Tsodikov

New Application of Neomycin B-Bisbenzimidazole Hybrids as Antifungal Agents.

DOI：
10.1021/acsinfecdis.7b00254
发表时间：
2018-02-09
期刊：
ACS infectious diseases
影响因子：
5.3
作者：
Thamban Chandrika N;Shrestha SK;Ranjan N;Sharma A;Arya DP;Garneau-Tsodikova S
通讯作者：
Garneau-Tsodikova S

Acetylation by Eis and Deacetylation by Rv1151c of Mycobacterium tuberculosis HupB: Biochemical and Structural Insight.

DOI：
10.1021/acs.biochem.7b01089
发表时间：
2018-02-06
期刊：
Biochemistry
影响因子：
2.9
作者：
Green KD;Biswas T;Pang AH;Willby MJ;Reed MS;Stuchlik O;Pohl J;Posey JE;Tsodikov OV;Garneau-Tsodikova S
通讯作者：
Garneau-Tsodikova S

A complex game of hide and seek: the search for new antifungals.