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
基本信息
- 批准号:8797302
- 负责人:
- 金额:$ 20.54万
- 依托单位:
- 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 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:A MouseAminesAnimal ModelAntibiotic ResistanceAntibioticsAreaBacteroidesBenzeneBifidobacteriumBiochemistryBiological AssayBiological AvailabilityCampylobacterCarbapenemsCephalosporinsChemicalsChronicChronic DiseaseCiprofloxacinClinicClinicalClinical TrialsClostridiumClostridium difficileCoupledCouplingCryptosporidiumCryptosporidium parvumDrug EvaluationDrug TargetingDrug resistanceDrug resistance pathwayDysenteryEntamoebaEntamoeba histolyticaEnteralEnzymatic BiochemistryEnzymesEpsilonproteobacteriaFDA approvedFluoroquinolonesFuransGenerationsGiardiaGiardia lambliaHealthHelicobacterHelicobacter InfectionsHelicobacter pyloriHumanHybridsIn VitroInfectionInterventionLactic acidLactobacillusLeadLifeMetabolismMethodsModelingMusMutationNitroreductasesOxidation-ReductionParasitesParasitic infectionParasitologyParentsPharmaceutical ChemistryPharmaceutical PreparationsPhasePhase I Clinical TrialsPhase II Clinical TrialsPredispositionProbioticsPropylaminesProteobacteriaPyruvate synthaseRecurrenceRefractoryResearchResistanceSafetyStructureStructure-Activity RelationshipStudy modelsSystemic infectionTestingTherapeuticThiamineThiamine PyrophosphateThiazolesThiophenesToxic effectToxicologyTreatment EfficacyTrichomonasTrichomonas vaginalisVaginaValidationVancomycinVitaminsWeaninganalogantimicrobialantimicrobial drugbasecofactordeprotonationdesigndrug efficacyefficacy testingfluoroformimprovedin vivomeetingsmembermicrobialmouse modelmulti-drug resistant pathogenmutantnew therapeutic targetnext generationnitazoxanidenovelnovel therapeuticsoxidoreductase inhibitorpathogenpreclinical evaluationscale upsuccesstherapeutic target
项目摘要
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:铁氧还蛋白氧化还原酶(PFOR)是所有严格厌氧细菌、厌氧人类寄生虫和嗜热变形菌(螺杆菌和弯曲杆菌)中的中枢代谢必需酶。Amixicile是我们团队开发的一流的氨基-硝基噻唑丙胺抗生素,特异性抑制PFOR和相关酶,其中机械酶学和建模研究都表明化学抑制机制涉及活化的焦磷酸硫胺素(TPP,维生素B1的衍生物)辅因子的去质子化,从而使PFOR催化循环失活1。意义:这种机制似乎可以逃避基于突变的耐药性,因为对TPP等维生素的化学变化被认为是致命的。重要的是,在艰难梭菌临床分离株中或通过体外突变体产生方法用H.幽门。Amixicile不具有氧化还原活性、致突变性或硝基还原酶的底物;与FDA批准的母体药物硝唑尼特(NTZ)相比,其表现出更高的靶向选择性、生物利用度和更低的毒性。Amixicile是针对C.在艰难梭菌感染(CDI)中,并且在小鼠CDI模型中,被认为是人类疗效的预测,阿莫西西莱在5天时显示出优于NTZ和与标准疗法(非达霉素和万古霉素)等效,并且在第14天时优于两种药物,没有CDI复发。Amixicile不会损害有益的益生菌微生物群。Amixicile已完成临床前评估,具有出色的药理学指标(ADME,毒理学和PK),并正在进行I期临床试验。拟议的研究将验证PFOR药物靶点,并评估amixicile对隐孢子虫、蓝氏贾第鞭毛虫、迷走毛滴虫、溶组织内阿米巴和幽门螺杆菌的治疗效果,以满足“可行性或用于新的干预目标,并进行先导药物优化和筛选
更有效的类似物”。我们组建了一个由药物化学、寄生虫学、微生物生物化学和动物模型专家组成的合作团队,并开发了一种管道方法,以快速跟踪第二代先导化合物,如下文R21和R33使能研究的具体目标所述。这些研究的R21阶段将包括:目的1,在微小隐孢子虫、蓝氏贾第鞭毛虫、溶组织内阿米巴和幽门螺杆菌感染的小鼠模型中评价amixicile;目的2,通过构效关系进行amixicile的药物化学导向先导优化,并开始探索
基于从环丙沙星成功制备环丙噻唑的基础上,将氨基硝基噻唑应用于现有抗生素,目标3将通过对阿莫西西开发的先导化合物和目标2中创建的新型多靶点疗法进行体外和体内测试来完成研究的R33部分。新类似物的疗效研究和初步PK研究将优先用于进一步的临床前评价。我们开发针对维生素辅因子和多种药物靶点的新疗法的策略旨在克服典型的耐药性途径。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 影响因子:2
- 作者:Jain,Eisha;Zaenker,EdnaI;Hoffman,PaulS;Warren,CirleA
- 通讯作者:Warren,CirleA
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Cirle Alcantara Warren其他文献
TRPV4 modulates inflammatory responses and apoptosis in enteric glial cells triggered by Clostridioides difficile toxins A and B
- DOI:
10.1186/s12950-024-00425-7 - 发表时间:
2025-01-14 - 期刊:
- 影响因子:4.100
- 作者:
Dvison de Melo Pacífico;Deiziane Viana da Silva Costa;Maria Lucianny Lima Barbosa;Conceição Silva Martins Rebouças;Simone de Goes Simonato;Cirle Alcantara Warren;Maria Luana Gaudencio dos Santos Morais;Renata Ferreira de Carvalho Leitao;Gerly Anne de Castro Brito - 通讯作者:
Gerly Anne de Castro Brito
<em>Clostridium difficile</em> and <em>Entamoeba histolytica</em> infections in patients with colitis in the Philippines
- DOI:
10.1016/j.trstmh.2012.04.005 - 发表时间:
2012-07-01 - 期刊:
- 影响因子:
- 作者:
Cirle Alcantara Warren;Eternity Labio;Raul Destura;Jesus Emmanuel Sevilleja;Jade D. Jamias;Ma. Lourdes O. Daez - 通讯作者:
Ma. Lourdes O. Daez
Effects of adenosine A2A receptor activation and alanyl-glutamine in Clostridium difficile toxin-induced ileitis in rabbits and cecitis in mice
- DOI:
10.1186/1471-2334-12-13 - 发表时间:
2012-01-20 - 期刊:
- 影响因子:3.000
- 作者:
Cirle Alcantara Warren;Gina M Calabrese;Yuesheng Li;Sean W Pawlowski;Robert A Figler;Jayson Rieger;Peter B Ernst;Joel Linden;Richard L Guerrant - 通讯作者:
Richard L Guerrant
Cirle Alcantara Warren的其他文献
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{{ truncateString('Cirle Alcantara Warren', 18)}}的其他基金
Disulfiram for Entameoba histolytica Enteric Diarrhea [DEED] Trial
双硫仑治疗溶组织内阿米巴肠腹泻 [DEED] 试验
- 批准号:
10328369 - 财政年份:2022
- 资助金额:
$ 20.54万 - 项目类别:
Alanyl-glutamine supplementation of standard treatment for C. difficile infection
补充丙氨酰谷氨酰胺作为艰难梭菌感染的标准治疗方法
- 批准号:
10214449 - 财政年份:2020
- 资助金额:
$ 20.54万 - 项目类别:
Alanyl-glutamine supplementation of standard treatment for C. difficile infection
补充丙氨酰谷氨酰胺作为艰难梭菌感染的标准治疗方法
- 批准号:
10443734 - 财政年份:2020
- 资助金额:
$ 20.54万 - 项目类别:
Alanyl-glutamine supplementation of standard treatment for C. difficile infection
补充丙氨酰谷氨酰胺作为艰难梭菌感染的标准治疗方法
- 批准号:
10670117 - 财政年份:2020
- 资助金额:
$ 20.54万 - 项目类别:
Alanyl-glutamine supplementation of standard treatment for C. difficile infection
补充丙氨酰谷氨酰胺作为艰难梭菌感染的标准治疗方法
- 批准号:
9887011 - 财政年份:2020
- 资助金额:
$ 20.54万 - 项目类别:
Adenosine receptor-mediated effects of Clostridium difficile toxins in humans
腺苷受体介导的艰难梭菌毒素对人体的影响
- 批准号:
9177910 - 财政年份:2016
- 资助金额:
$ 20.54万 - 项目类别:
Effects of alanyl-glutamine supplementation on C. difficile associated diarrhea
补充丙氨酰谷氨酰胺对艰难梭菌相关性腹泻的影响
- 批准号:
8669628 - 财政年份:2014
- 资助金额:
$ 20.54万 - 项目类别:
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