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Development of an Oral Carbapenem Drug for Treatment of Drug Resistant TB

开发治疗耐药结核病的口服碳青霉烯类药物

基本信息

批准号：
8703923
负责人：
Gyanu Lamichhane
金额：
$ 23.61万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703923
关键词：
Americas Anabolism Anti-Bacterial Agents Antibiotic Resistance Antibiotics Area Under Curve Bacteria Bacterial Infections Binding Bioavailable Biochemical Biological Availability Carbapenems Chemicals Clavulanate Clinical Communicable Diseases Data Defect Development Disease Drug Kinetics Drug Targeting Drug resistance Drug-sensitive Enzymes Epidemic Evolution FDA approved Future Goals Growth Half-Life Human In Vitro Infection Knowledge Label Lactamase Lactams Lead Manuscripts Microbial Antibiotic Resistance Molecular Mycobacterium tuberculosis Oral Peptidoglycan Peptidyltransferase Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Phase Phenotype Physicians Principal Investigator Prodrugs Property Publishing Recording of previous events Reporting Resistance Roentgen Rays Scientist Societies Staging Structure Testing Therapeutic Time United States Variant adduct antimicrobial base biophysical techniques cheminformatics combat design drug candidate drug development drug resistant bacteria enzyme pathway in vitro activity in vivo inhibitor/antagonist innovation killings mouse model novel pathogen public health relevance research study resistant strain scaffold transpeptidation

项目摘要

DESCRIPTION (provided by applicant): In 2008, leading infectious diseases physician scientists representing Infectious Diseases Society of America published a report titled "The Epidemic of Antibiotic-Resistant Infection" in which they declared "We are in the midst of an emerging crisis of antibiotic resistance for microbial pathogens in the United States and throughout the world." It is widely accepted that the only means to effectively combat the widespread evolution of bacterial pathogens to resist existing drugs is to innovate new drugs that inhibit novel targets. The peptidoglycan (PG) layer is considered the Achilles' Heel of bacteria and the drugs that inhibit the final step of its synthesis, namely the ¿-lactams, represen ~60% of all antibiotics in clinical use and therefore have the highest impact in treating bacterial infections in humans. The final step of the PG biosynthesis is catalyzed by 3,3- and 4,3-transeptidases. The ¿-lactams act by inhibiting 4,3-transpeptidases. However, there are no known agents that specifically inhibit 3,3-transpeptidases. We have shown that 3,3-transpeptidases are essential for M. tuberculosis to grow and cause disease and therefore comprise novel target for drug development. Can inhibiting this novel target usher us, once again, to a new era of effective antibacterial drugs? In this proposal we present the rationale, preliminary data, demonstrate that 3,3-transpeptidase is a novel target with the promise of a high-impact in treatment of bacterial infections and propose studies to achieve these goals. We and others have recently shown that carbapenems, a class of ¿-lactam drugs, binds and inhibits 3,3-transpeptidases. In this proposal we will test the hypothesis that variants based on the carbapenem structure can inhibit 3,3-transpeptidase activity and consequently kill M. tuberculosis. By focusing on 3,3- transpeptidase activity, an unexploited but validated drug target, we expect to develop new carbapenems that have activity against drug sensitive and resistant strains of M. tuberculosis.

描述（由申请人提供）：2008年，代表美国传染病学会的主要传染病内科科学家发表了一份题为《抗生素耐药性感染的流行》的报告，他们在报告中宣称：“我们正处于美国和全世界微生物病原体抗生素耐药性的新危机之中。”人们普遍认为，有效对抗细菌病原体广泛进化以抵抗现有药物的唯一手段是创新抑制新靶点的新药。肽聚糖（PG）层被认为是细菌的阿喀琉斯之踵，抑制其合成最后一步的药物，即内酰胺类，占临床使用的所有抗生素的60%，因此对治疗细菌的影响最大