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Repurposing novel selective drugs for treatment and decolonization of vancomycin resistant enterococci

重新利用新型选择性药物治疗万古霉素耐药肠球菌并使其去定植

基本信息

批准号：
10468002
负责人：
Mohamed Seleem
金额：
$ 61.96万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468002
关键词：
Acetazolamide Address Affinity Chromatography Animal Model Anti-Bacterial Agents Antibiotics Autoimmune Diseases Bacteria Binding Biological Assay Biotin Blood Blood Circulation Carbonic Anhydrase Inhibitors Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Chronic Clinic Colon Consumption Daptomycin Data Development Dorzolamide Dose Drug Design Drug Kinetics Drug resistance Endocarditis Enterococcus Event FDA approved Future Genes Genetic Glaucoma Health Care Costs Healthcare Healthcare Systems Homeostasis Human In Vitro Incidence Individual Infection Inflammation Investigational Drugs Label Lead Length of Stay Linezolid Medicine Methazolamide Methods Modeling Modification Morbidity - disease rate Multi-Drug Resistance Mus Neonatal Nosocomial Infections Oral Parkinson Disease Patients Pelvis Peritoneal Peritonitis Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Predisposition Prevalence Process Property Proteins Rattus Recombinants Resistance Risk Route Safety Severities Skin Structure Structure-Activity Relationship Testing Therapeutic Time Toxic effect United States Urinary tract Urinary tract infection Validation Vancomycin Vancomycin resistant enterococcus Virulent World Health Organization Wound Infection X-Ray Crystallography analog antibiotic resistant infections antimicrobial base clinical application combat cost drug development drug discovery drug repurposing dysbiosis effective therapy fighting genome sequencing gut microbiome gut microbiota health care settings improved in vivo inhibitor innovation insight knock-down lead optimization microbiome mortality mouse model mutant novel novel strategies novel therapeutics pathogen pathogenic bacteria readmission rates research clinical testing resistance mechanism resistant strain scaffold screening small molecule success therapeutically effective transmission process

项目摘要

Project Abstract: Vancomycin-resistant enterococci (VRE) is the second leading cause of drug-resistant hospital-acquired infections (HAIs) in the US, triggering the Centers for Disease Control and Prevention to classify VRE as a serious healthcare threat. Despite the prevalence and severity of VRE infections, there are limited number of effective therapeutic options available for treatment. Moreover, the drugs that are available are also detrimental to the normal gut microbiota ultimately contributing the problematic cycle of microbial imbalance known as dysbiosis, which enterococcus takes advantage of in the first place. Thus, there is a significant need for a treatment that can be used to clear both symptomatic and asymptomatic enterococcus colonization without damaging the homeostasis of normal gut flora. Unlike the costly and time-consuming process of de novo drug discovery, drug repurposing is a novel method to reduce the time, cost and risk associated with drug innovation. Studies proposed in this application build upon discoveries of the potent and narrow spectrum antimicrobial activity of the FDA-approved drugs, carbonic anhydrase inhibitors (CAIs) (acetazolamide, dorzolamide, brinzolamide, ethoxzolamide, methazolamide, and dichlorphenamide), in an applicable clinical range, against highly multidrug-resistant enterococci, including VRE. We have demonstrated both in vitro and in vivo that CAIs are superior to drug of choice, linezolid, and can be used for treatment of serious VRE infections as well as VRE decolonization without harming gut microbiota. In addition, we were able to identify a novel antimicrobial target specific for enterococci that could be exploited in future screening campaigns for new inhibitory scaffolds. Our team has embarked upon medicinal chemistry optimization and improved the potency of the scaffold versus VRE by 570-fold (MIC = 0.007 µg/ml for most potent analog) while maintaining no antibacterial activity against normal gut microbiota. We propose to continue lead optimization and assess the in vivo efficacy in various VRE mouse models as well evaluate the novel inhibitor’s safety and PK profiles to support future lead selection and investigational new drug enabling studies.

项目简介: