Novel Spectinamide Antibiotics for the Treatment of MDR/XDR Tuberculosis
用于治疗 MDR/XDR 结核病的新型 Spectinamide 抗生素
基本信息
- 批准号:8436177
- 负责人:
- 金额:$ 29.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-03-01 至 2014-05-28
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAdverse effectsAdvocateAerosolsAmikacinAminoglycosidesAmoxicillinAnti-Bacterial AgentsAntibiotic ResistanceAntibiotic TherapyAntibioticsAntimycobacterial AgentsAntitubercular AgentsBackBacteriaBacterial ProteinsBindingBiological AssayBiological FactorsCapromycinCause of DeathCell LineCellsCessation of lifeCharacteristicsChemicalsChemistryClarithromycinClavulanateClinicalCollaborationsCommunicable DiseasesDeath RateDeveloping CountriesDevelopmentDiseaseDoseDrug KineticsDrug Resistant TuberculosisEthambutolExtreme drug resistant tuberculosisFDA approvedFluoroquinolonesGoalsHIVHumanImipenemImmunocompromised HostIn VitroIncidenceIndividualInfectionInjectableKanamycinLaboratoriesLeadLinezolidLocationMammalian CellMammalsMedicalMetabolicModificationMolecular WeightMoxifloxacinMulti-Drug ResistanceMultidrug-Resistant TuberculosisMusMycobacterium tuberculosisNeisseria gonorrhoeaePatientsPharmaceutical PreparationsPharmacologyPhasePopulationProcessProductionPropertyProtein BiosynthesisProtein Synthesis InhibitionPyrazinamideResearchResearch Project GrantsResistanceRibosomesRifampinRouteSafetySaint Jude Children&aposs Research HospitalSeriesSiteSolubilitySpectinomycinStreptomycinSynthesis ChemistryTestingTherapeuticTherapeutic AgentsTherapeutic IndexTimeToxic effectToxicologyTreatment ProtocolsTuberculosisVirulentWorld Health Organizationalternative treatmentanalogbactericideclinical materialcompliance behaviorcytotoxicitydrug discoveryimprovedin vitro activityin vivoisoniazidmacrophagenovelpathogenpre-clinicalpreclinical studyresearch studyresistant strainscaffoldscale uptreatment durationtuberculosis treatment
项目摘要
DESCRIPTION (provided by applicant): The overall objective of this project is to further develop a novel chemical class of tuberculosis (TB) therapeutic agents, the spectinamide series, for use against MDR and XDR strains of Mycobacterium tuberculosis (Mtb) and identify, through a series of in vitro and in vivo assays, a preclinical candidate. TB is a lethal infectious disease, second only to HIV/AIDS as a cause of death. Estimates by the World Health Organization show one-third of the world population is infected with Mtb, the bacterium that causes TB; approximately 10% of infected individuals will develop active TB at some time in their lives. Of recent concern is the rising number of TB cases involving strains that are multidrug-resistant (MDR), which is defined as being resistant to treatment with isoniazid and rifampicin, the two first-line antibiotics for TB therapy and those that are extensively drug-resistant tuberculosis [XDR TB; defined as being resistant to isoniazid and rifampicin (as for MDR TB) and also to any fluoroquinolone and at least one of the three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin)]. Treatment options for MDR/XDR TB include the two remaining first- line agents, ethambutol and pyrazinamide, second-line agents to which the strain is not resistant, such as streptomycin, as well as unproven agents such as linezolid, amoxicillin/clavulanate, clarithromycin, clofazimine and imipenem. Research suggests that at least four drugs and 18-24 month duration of treatment may be required for successful therapy of XDR TB; however, toxicity of the agents may preclude patients from being effectively treated. There is a clear unmet medical need for efficacious and safe drugs to be used as treatment for MDR/XDR TB. The novel spectinomycin analogs outlined in this proposal possess potent in vitro activity against MDR/XDR TB (MIC 0.4-1.6 5g/mL), act via a bactericidal mechanism of action, have demonstrated ability to enter macrophages, the host location of TB infections, and are safe compounds, displaying low in vitro cytotoxicity and no observed in vivo toxicity. These overall characteristics advocate for the rapid development of these compounds as a safe alternative treatment for drug resistant TB. We will, in conjunction with our collaborators, Dr. Richard Lee and Helena Boshoff, characterize the in vitro properties of the spectinamide class, including potency against MDR/XDR TB isolates, minimum toxicity against mammalian cell lines and metabolic stability. We will, then scale-up the synthesis of the most favorable analogs for in vivo studies and optimize the synthetic chemistry route in the process. Finally, in collaboration with Dr. Anne Lenaerts, we will evaluate in vivo toxicology, pharmacokinetics and efficacy in mice. These experiments will allow us to identify a final lead and backup compound suitable for advancement to Phase II. In Phase II, we will conduct long term in vivo efficacy studies of the preclinical candidate, both as monotherapy and in combination with anti-TB agents for MDR-TB. We will also conduct pharmacokinetic studies, GLP toxicology and safety pharmacology studies to select a final anti-MDR/XDR clinical candidate suitable for IND submission.
描述(由申请人提供):该项目的总体目标是进一步开发一种新型化学类别的结核病(TB)治疗剂--spectinamide系列,用于对抗结核分枝杆菌(Mtb)的MDR和XDR菌株,并通过一系列体外和体内试验确定临床前候选药物。结核病是一种致命的传染病,是仅次于艾滋病毒/艾滋病的死因。世界卫生组织的估计显示,世界上三分之一的人口感染了结核分枝杆菌,这种细菌会导致结核病;大约10%的感染者会在一生中的某个时候患上活动性结核病。最近令人关切的是,涉及多药耐药(MDR)菌株的结核病病例不断增加,耐多药菌株的定义是耐异烟肼和利福平,这两种抗生素是结核病治疗的两种一线抗生素,而广泛耐药结核病[XDR TB;定义为对异烟肼和利福平耐药(与耐多药结核病一样)以及任何氟喹诺酮和至少三种可注射二线药物(即阿米卡星、卡那霉素或卷曲霉素)中的至少一种)]。耐多药/广泛耐药结核的治疗选择包括剩下的两种一线药物,乙胺丁醇和吡嗪酰胺,菌株不耐药的二线药物,如链霉素,以及未经证实的药物,如利奈唑胺、阿莫西林/克拉维酸、克拉霉素、氯法齐明和亚胺培南。研究表明,成功治疗广泛耐药结核病可能需要至少四种药物和18-24个月的疗程;然而,这些药物的毒性可能会阻碍患者得到有效的治疗。对于用于治疗耐多药/广泛耐药结核病的有效和安全的药物,显然存在未得到满足的医疗需求。新的壮观霉素类似物对MDR/XDR TB具有较强的体外抗MDR/XDR TB活性(MIC 0.4~1.6 5g/mL),通过杀菌作用机制发挥作用,具有进入巨噬细胞的能力,是结核感染的宿主部位,是安全的化合物,体外细胞毒性低,体内没有观察到的毒性。这些总体特征促使这些化合物迅速发展,成为耐药结核病的安全替代治疗方法。我们将与我们的合作者Richard Lee博士和Helena Boshoff博士一起研究spectinide类别的体外特性,包括对MDR/XDR TB分离株的效力、对哺乳动物细胞系的最低毒性和代谢稳定性。然后,我们将扩大最有利于体内研究的类似物的合成,并在此过程中优化合成化学路线。最后,我们将与安妮·勒纳尔茨博士合作,在小鼠身上评估体内毒理学、药代动力学和疗效。这些实验将使我们能够确定适合进入第二阶段的最终先导和后备化合物。在第二阶段,我们将对临床前候选药物进行长期体内疗效研究,无论是作为单一疗法还是与抗结核药物联合治疗耐多药结核病。我们还将进行药代动力学研究、GLP毒理学和安全药理学研究,以选择适合IND提交的最终抗MDR/XDR临床候选药物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Michelle M. Butler其他文献
Midwifery education in Canada
- DOI:
10.1016/j.midw.2015.11.019 - 发表时间:
2016-02-01 - 期刊:
- 影响因子:
- 作者:
Michelle M. Butler;Eileen K. Hutton;Patricia S. McNiven - 通讯作者:
Patricia S. McNiven
Michelle M. Butler的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Michelle M. Butler', 18)}}的其他基金
Oxadiazole Inhibitors of Non-Stop Ribosome Rescue to treat MDR Neisseria gonorrhoeae
不间断核糖体救援恶二唑抑制剂治疗耐多药淋病奈瑟菌
- 批准号:
10231210 - 财政年份:2017
- 资助金额:
$ 29.11万 - 项目类别:
Aminospectinomycin antibacterials for the treatment of antibiotic-resistant gonorrhea and other bacterial STDs
氨基大观霉素抗菌药用于治疗抗生素耐药性淋病和其他细菌性 STD
- 批准号:
9252872 - 财政年份:2017
- 资助金额:
$ 29.11万 - 项目类别:
Novel spectinamide antibiotics for the treatment of MDR/XDR tuberculosis
用于治疗 MDR/XDR 结核病的新型大观酰胺抗生素
- 批准号:
8857368 - 财政年份:2012
- 资助金额:
$ 29.11万 - 项目类别:
Novel spectinamide antibiotics for the treatment of MDR/XDR tuberculosis
用于治疗 MDR/XDR 结核病的新型大观酰胺抗生素
- 批准号:
8714556 - 财政年份:2012
- 资助金额:
$ 29.11万 - 项目类别:
Novel Spectinamide Antibiotics for the Treatment of MDR/XDR Tuberculosis
用于治疗 MDR/XDR 结核病的新型 Spectinamide 抗生素
- 批准号:
10252947 - 财政年份:2012
- 资助金额:
$ 29.11万 - 项目类别:
Novel Plasmodial Surface Anion Channel Inhibitors as Antimalarial Drugs
作为抗疟药物的新型疟原虫表面阴离子通道抑制剂
- 批准号:
10062806 - 财政年份:2012
- 资助金额:
$ 29.11万 - 项目类别:
Novel Plasmodial Surface Anion Channel Inhibitors as Antimalarial Drugs
作为抗疟药物的新型疟原虫表面阴离子通道抑制剂
- 批准号:
8549102 - 财政年份:2012
- 资助金额:
$ 29.11万 - 项目类别:
Novel Plasmodial Surface Anion Channel Inhibitors as Antimalarial Drugs
作为抗疟药物的新型疟原虫表面阴离子通道抑制剂
- 批准号:
8832349 - 财政年份:2012
- 资助金额:
$ 29.11万 - 项目类别:
Novel Plasmodial Surface Anion Channel Inhibitors as Antimalarial Drugs
作为抗疟药物的新型疟原虫表面阴离子通道抑制剂
- 批准号:
8311901 - 财政年份:2012
- 资助金额:
$ 29.11万 - 项目类别:
Novel Spectinamide Antibiotics for the Treatment of MDR/XDR Tuberculosis
用于治疗 MDR/XDR 结核病的新型 Spectinamide 抗生素
- 批准号:
8250690 - 财政年份:2012
- 资助金额:
$ 29.11万 - 项目类别:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
$ 29.11万 - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
$ 29.11万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
$ 29.11万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
$ 29.11万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
$ 29.11万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
$ 29.11万 - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
$ 29.11万 - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
$ 29.11万 - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
$ 29.11万 - 项目类别:
Adverse Effects of Using Laser Diagnostics in High-Speed Compressible Flows
在高速可压缩流中使用激光诊断的不利影响
- 批准号:
RGPIN-2018-04753 - 财政年份:2022
- 资助金额:
$ 29.11万 - 项目类别:
Discovery Grants Program - Individual