PFOR inhibitor amixicile for treatment of drug resistant parasites and bacteria

PFOR 抑制剂 amixicile 用于治疗耐药寄生虫和细菌

• 批准号: 8797302
• 负责人: Cirle Alcantara Warren
• 金额: $ 20.54万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8797302
• 关键词: A Mouse; Amines; Animal Model; Antibiotic Resistance; Antibiotics; Area; Bacteroides; Benzene; Bifidobacterium; Biochemistry; Biological Assay; Biological Availability; Campylobacter; Carbapenems; Cephalosporins; Chemicals; Chronic; Chronic Disease; Ciprofloxacin; Clinic; Clinical; Clinical Trials; Clostridium; Clostridium difficile; Coupled; Coupling; Cryptosporidium; Cryptosporidium parvum; Drug Evaluation; Drug Targeting; Drug resistance; Drug resistance pathway; Dysentery; Entamoeba; Entamoeba histolytica; Enteral; Enzymatic Biochemistry; Enzymes; Epsilonproteobacteria; FDA approved; Fluoroquinolones; Furans; Generations; Giardia; Giardia lamblia; Health; Helicobacter; Helicobacter Infections; Helicobacter pylori; Human; Hybrids; In Vitro; Infection; Intervention; Lactic acid; Lactobacillus; Lead; Life; Metabolism; Methods; Modeling; Mus; Mutation; Nitroreductases; Oxidation-Reduction; Parasites; Parasitic infection; Parasitology; Parents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Predisposition; Probiotics; Propylamines; Proteobacteria; Pyruvate synthase; Recurrence; Refractory; Research; Resistance; Safety; Structure; Structure-Activity Relationship; Study models; Systemic infection; Testing; Therapeutic; Thiamine; Thiamine Pyrophosphate; Thiazoles; Thiophenes; Toxic effect; Toxicology; Treatment Efficacy; Trichomonas; Trichomonas vaginalis; Vagina; Validation; Vancomycin; Vitamins; Weaning; analog; antimicrobial; antimicrobial drug; base; cofactor; deprotonation; design; drug efficacy; efficacy testing; fluoroform; improved; in vivo; meetings; member; microbial; mouse model; multi-drug resistant pathogen; mutant; new therapeutic target; next generation; nitazoxanide; novel; novel therapeutics; oxidoreductase inhibitor; pathogen; preclinical evaluation; scale up; success; therapeutic target

DESCRIPTION (provided by applicant): Pyruvate: ferredoxin oxidoreductase (PFOR) is an essential enzyme of central metabolism in all strictly anaerobic bacteria, anaerobic human parasites and in epsilon proteobacteria (Helicobacter and Campylobacter). Amixicile, a first-in-class amino-nitrothiazole propylamine antibiotic developed by our team, specifically inhibits PFOR and related enzymes, where both mechanistic enzymology and modeling studies suggest a chemical inhibition mechanism involving deprotonation of the activated thiamine pyrophosphate (TPP, a derivative of vitamin B1) cofactor, thus inactivating the PFOR catalytic cycle1. Significance: This mechanism appears to escape mutation based drug resistance as chemical changes to vitamins like TPP are believed to be lethal. Importantly, resistance to amixicile has not been observed with Clostridium difficile clinical isolates or through in vitro mutant generation methods with H. pylori. Amixicile is not redox-active, mutagenic or a substrate of nitroreductases; and demonstrates greater target selectivity, bioavailability and lower toxicity compared to parent FDA-approved drug nitazoxanide (NTZ). Amixicile was developed to treat C. difficile infections (CDI) and in a mouse CDI model, considered predictive of human efficacy, amixicile showed superiority to NTZ and equivalence to standard therapies (fidaxomicin and vancomycin) at 5 days and superiority over both drugs by day 14 with no recurrence of CDI. Amixicile does not harm beneficial probiotic microflora. Amixicile has completed preclinical evaluation with excellent pharmacological metrics (ADME, toxicology and PK) and is on track for phase 1 clinical trials. The proposed studies will validate the PFOR drug target and assess therapeutic efficacy of amixicile against Cryptosporidium parvum, Giardia lamblia, Trichomonas vaginalis, Entamoeba histolytica and Helicobacter pylori to meet the "feasibility or use in new interventions objective, and for lead optimization and screens to evolve more potent analogues". We have assembled a collaborative team of experts in medicinal chemistry, parasitology, microbial biochemistry and animal models and have developed a pipeline approach to fast track second generation leads as outlined below in the specific aims for R21 and R33 enabling studies. The R21 phase of these studies will include: Aim 1 to evaluate amixicile in mouse models of infection for Cryptosporidium parvum, Giardia lamblia, Entamoeba histolytica, and Helicobacter pylori; Aim 2 performs a medicinal chemistry directed lead optimization of amixicile by structure activity relationships and begins exploring coupling of amino nitro-thiazole to existing antibiotics based on the success of creating ciprothiazole from ciprofloxacin and aim 3 will complete the R33 portion of the studies by in vitro and in vivo testin of developed leads from amixicile and novel multi- target therapeutics created in Aim 2. Efficacy studies and preliminary PK studies with new analogues will be prioritized for further preclinical evaluation. Our strategy of developing new therapeutics that target vitamin cofactors and multiple drug targets is designed to overcome typical pathways of drug resistance.

描述（由申请人提供）：丙酮酸：铁蛋白氧化还原酶（PFOR）是所有严格的厌氧细菌，厌氧人类寄生虫和epsilon proteeobacteria（Helicobacter and helicobacter and Campylobacter）中中枢代谢的必要酶。 Amixicile, a first-in-class amino-nitrothiazole propylamine antibiotic developed by our team, specifically inhibits PFOR and related enzymes, where both mechanistic enzymology and modeling studies suggest a chemical inhibition mechanism involving deprotonation of the activated thiamine pyrophosphate (TPP, a derivative of vitamin B1) cofactor, thus inactivating the PFOR catalytic cycle1.意义：这种机制似乎避免了基于突变的耐药性，因为据信像TPP这样的维生素变化是致命的。重要的是，尚未使用艰难梭菌临床分离株或幽门螺杆菌的体外突变产生方法观察到对阿米克西菌的耐药性。阿米克斯不是氧化还原活性，诱变或硝基还原酶的底物。与母体FDA批准的Nitazoxanide（NTZ）相比，证明了更大的靶标选择性，生物利用度和较低的毒性。开发了阿米克西菌以治疗艰难梭菌感染（CDI），在被认为可以预测人类功效的小鼠CDI模型中，阿米克西菌在5天（Fidaxomicin和Vancomycin）在5天（Fidaxomicin和Vancomycin）上表现出优越性，并且在两种药物中都没有CDI复发的第14天，并且在两种药物上都具有优势。阿米克斯不损害有益的益生菌菌群。 Amixicile已通过出色的药理学指标（ADME，毒理学和PK）完成了临床前评估，并正在努力进行1期临床试验。 The proposed studies will validate the PFOR drug target and assess therapeutic efficacy of amixicile against Cryptosporidium parvum, Giardia lamblia, Trichomonas vaginalis, Entamoeba histolytica and Helicobacter pylori to meet the "feasibility or use in new interventions objective, and for lead optimization and screens to evolve 更有效的类似物”。我们已经组建了一支由药物化学，寄生虫学，微生物生物化学和动物模型的专家组成的团队，并开发了一种管道方法，以快速轨道第二代的介绍，如下所述，在R21和R33的特定目的中概述了这些研究的研究。贾第鞭毛虫lamblia，entamoeba Histolictica和幽门螺杆菌2; 基于基于环丙沙星和AIM 3创建环噻唑的成功的成功，将通过体外和体内测试中的R33部分来完成R33的部分研究，从而在AIM 2中创建了AIM和PRELINALITIAL PRELICAL PRETUPE和PRELERIANS PRETUPE，这是由新颖的多目标治疗方法。我们开发靶向维生素辅助因子和多种药物靶标的新疗法的策略旨在克服典型的耐药性途径。

项目成果

In vitro activity of amixicile against T. vaginalis from clinical isolates.

amixicile 对临床分离株阴道毛滴虫的体外活性。

• DOI: 10.1007/s00436-022-07567-8
• 发表时间: 2022
• 期刊: Parasitology research
• 影响因子: 2
• 作者: Jain,Eisha;Zaenker,EdnaI;Hoffman,PaulS;Warren,CirleA
• 通讯作者: Warren,CirleA