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: 8115981
• 负责人: PAUL Stokes HOFFMAN
• 金额: $ 53.49万
• 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/8115981
• 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; 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; FDA approved; Ferredoxin; Flavodoxin; Food; Generations; Generic Drugs; Giardia lamblia; Goals; Hamsters; Human; In Vitro; Inbred C3H Mice; 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; Parasites; Parasitology; Pharmaceutical Chemistry; Phase; Process; Prodrugs; Production; Property; Prophylactic treatment; Protocols documentation; Publishing; Pyruvate; Pyruvate synthase; Research; Research Personnel; Screening procedure; Site; Staging; Testing; Therapeutic; Therapeutic Index; Thiamine Pyrophosphate; Thiazoles; Titrations; Toxic effect; Toxicology; Treatment Efficacy; Universities; Variant; Virginia; Virulence; Water; Work; X-Ray Crystallography; Yeasts; base; biodefense; cofactor; commercialization; cytotoxicity; design; drug candidate; drug development; drug metabolism; efficacy testing; enteric pathogen; enteroaggregative Escherichia coli; fitness; improved; industry partner; inhibitor/antagonist; mouse model; nitazoxanide; novel; pathogen; pre-clinical; preclinical evaluation; product development; 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)： 拟议工作的研究重点是开发第二代广谱5-硝基噻唑类药物，以对抗B类优先食源性和水源性病原体微小隐孢子虫、溶组织内阿米巴、肠贾第鞭毛虫、空肠弯曲杆菌和梭状芽孢杆菌。所有这些人类病原体都有一个共同的和必要的中枢代谢代谢酶，丙酮酸铁氧还蛋白氧化还原酶(PFOR)，被认为是一个很好的药物靶点。我们已发表的和初步的研究证实，仿制药硝唑尼特(NTZ)是FDA批准用于治疗由微小弧菌和肠球菌引起的感染的一种5-硝基噻唑烷，通过一种新的机制选择性地抑制所有目标病原体的PFOR。机理研究表明，亚硝基噻唑阴离子解离了丙酮酸-硫胺素焦磷酸过渡中间体，从而阻止了乙酰辅酶A的形成，降低了还原能力。在这个过程中，ntz被质子化为非活性形式。硝唑尼特的生物活性高度依赖于pH，本研究的目标是开发在较低pH下更有效的衍生物。开发第二代广谱治疗药物的流水线方法包括以下具体目标：(I)在PKA知识和来自X射线结晶学的结构数据的推动下合成新的先导化合物，并在中通量PFOR 96孔法(IC50和KI)中筛选抑制活性；(Ii)在体外筛选对目标病原体具有生物活性的活性先导化合物(MIC、MBC、MLC)；(Iii)在动物感染模型中确定有效先导化合物的治疗效果；以及(Iv)通过产品开发、毒理学和扩大临床试验的规模来研究可行的候选药物。这个新的靶点和抑制机制有两个意想不到的警告：(I)发生耐药性的可能性低，(Ii)对肠道病原体的NAD-丙酮酸脱氢酶活性较弱-丧失适合性和定植效率。这些研究的成功完成将产生第二代广谱亚硝噻唑类药物，这些药物具有更高的生物利用度和对抗B类肠道寄生虫和细菌(广谱止泻剂)的效力，可以在临床上对生物恐怖主义活动或自然事件造成的感染的预防和初级治疗进行评估。

项目成果

Amixicile: A Concept Therapeutic for Treatment of Chronic Anaerobic Infections.

Amixicile：一种治疗慢性厌氧菌感染的概念疗法。

• DOI: 10.31488/bjg.1000108
• 发表时间: 2020
• 期刊: British journal of gastroenterology
• 作者: Hoffman,PaulS

Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model.

Amixicile 是一种新型丙酮酸：铁氧还蛋白氧化还原酶抑制剂，在小鼠感染模型中显示出对抗艰难梭菌的功效。

• DOI: 10.1128/aac.00360-12
• 发表时间: 2012
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Warren,CirleA;vanOpstal,Edward;Ballard,TEric;Kennedy,Andrew;Wang,Xia;Riggins,Mary;Olekhnovich,Igor;Warthan,Michelle;Kolling,GlynisL;Guerrant,RichardL;Macdonald,TimothyL;Hoffman,PaulS
• 通讯作者: Hoffman,PaulS