Nitrothiazolides:Broad-Spectrum Category B Anti-parasitic/bacterial Therapeutics

硝基噻唑类：广谱 B 类抗寄生虫/细菌治疗药物

• 批准号: 7325362
• 负责人: PAUL Stokes HOFFMAN
• 金额: $ 49.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7325362
• 关键词: Acetyl Coenzyme A; Adverse effects; Animal Model; Animals; Anions; Bacteria; Biochemical; Biological; Biological Assay; Biological Availability; Bioterrorism; Campylobacter jejuni; Categories; Cell Line; Chemical Structure; Chemicals; Chemistry; Class; Clinic; Clinical Trials; Clostridium; Clostridium difficile; Clostridium perfringens; Collection; Complex; Cryptosporidium; Cryptosporidium parvum; Crystallography; Data; Development; Dose; Drug Kinetics; Drug resistance; Entamoeba histolytica; Enteral; Enzymatic Biochemistry; Enzymes; Escherichia coli EHEC; Evaluation; Event; Exhibits; Ferredoxin; Flavodoxin; Food; Generations; Generic Drugs; Giardia lamblia; Goals; Hamsters; Human; In Vitro; Industry; Infection; Inhibitory Concentration 50; Intestines; Kinetics; Knowledge; Laboratories; Lead; Legal patent; Mammalian Cell; Measures; Medicine; Metabolic; Metabolism; Metronidazole; Metronidazole resistance; Microbiology; Modeling; Modification; Mutation; National Institute of Allergy and Infectious Disease; Newborn Infant; Organism; Oxidation-Reduction; Oxidoreductase; Pan Genus; Parasites; Parasitology; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Process; Prodrugs; Production; Property; Prophylactic treatment; Propionibacterium acnes; Protocols documentation; Publishing; Pyruvate; Pyruvate synthase; Pyruvates; Range; Research; Research Personnel; Screening procedure; Site; Staging; Testing; Therapeutic; Therapeutic Corynebacterium Parvum; Therapeutic Index; Thiamine Pyrophosphate; Thiazoles; Titrations; Toxic effect; Toxicology; Treatment Efficacy; United States Food and Drug Administration; Universities; Variant; Virginia; Virulence; Water; Work; X-Ray Crystallography; Yeasts; base; biodefense; cofactor; commercialization; cytotoxicity; design; drug development; drug metabolism; enteric pathogen; enteroaggregative Escherichia coli; fitness; improved; inhibitor/antagonist; mecarzole; mouse model; nitazoxanide; novel; pathogen; pre-clinical; programs; pyruvate dehydrogenase; resistance mechanism; salicylate; scale up; tool

DESCRIPTION (provided by applicant): The research focus of the proposed work is to develop second generation broad spectrum 5-nitrothiazolide therapeutics against Category B priority food and water borne pathogens Cryptosporidium parvum, Entamoeba histolytica, Giardia intestinalis, Campylobacter jejuni and Clostridium spp. All of these human pathogens share a common and essential metabolic enzyme of central metabolism, pyruvate ferredoxin oxidoreductase (PFOR) that is recognized as a good druggable target. Our published and preliminary studies establish that generic drug nitazoxanide (NTZ), a 5-nitrothiazolide which is FDA approved for treatment of infections caused by C. parvum and G. intestinalis, selectively inhibits PFOR in all of the target pathogens by a novel mechanism. Mechanistic studies show that the nitrothiazolide anion dissociates the pyruvate-thiamine pyrophosphate transition intermediate and thereby blocking formation of acetyl-CoA and reducing power. In the process, NTZ is protonated to an inactive form. The biological activity of nitazoxanide is highly pH dependent and the goal of the proposed studies is to develop derivatives which are more potent at lower pH. The pipeline approach to developing second generation broad spectrum therapeutics includes the following specific aims: (i) synthesize new lead compounds driven by knowledge of pKa and structural data from X-ray crystallography and screen for inhibitory activity in medium throughput PFOR 96 well assay (IC50 and Ki); (ii)screen active leads for biological activity against target pathogens in vitro (MIC, MBC, MLC); (iii) determine therapeutic efficacy of potent leads in animal infection models; and (iv) progress viable candidate drugs through product development, toxicology and scale up for clinical trials. Two unexpected caveats of this novel target and inhibitory mechanism are (i) low likelihood for development of drug resistance and (ii) weak activity against the NAD-pyruvate dehydrogenase of enteric pathogens - loss of fitness and colonization efficiency. Successful completion of these studies will produce second generation broad spectrum nitrothiazolide therapeutics with increased bioavailability and potency against Category B intestinal parasites and bacteria (broad spectrum anti-diarrheal agent) that can be evaluated clinically for prophylaxis against and primary treatment of infections caused by bioterrorism activities or natural events.

描述（由申请人提供）：