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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：
9403837
负责人：
Sylvie Garneau-Tsodikova
金额：
$ 53.6万
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9403837
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 Drug-sensitive 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 experience extensive drug resistance genome sequencing inhibitor/antagonist innovation interest killings 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.

摘要