Development of a mechanistically novel synergistic adjuvant to partner with polymyxin antibiotics

开发一种与多粘菌素抗生素配合使用的新型机械协同佐剂

基本信息

  • 批准号:
    10481682
  • 负责人:
  • 金额:
    $ 30万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Acinetobacter baumannii (Ab) and related spp. cause severe nosocomial pneumonia, wound, blood, and urinary tract infections, with mortality rates ranging from 25-75%. The emergence of multidrug-resistant (MDR) Ab isolates has made it difficult to treat with most standard-of-care antibiotics. Carbapenems have served as the preferred therapy to treat Ab infections, however, over 50% of infections are now carbapenem-resistant Ab (CRAB). Consequently, the WHO and CDC have classified CRAB as a PRIORITY-1 CRITICAL and URGENT threat pathogen. Polymyxin B (PMB) and colistin have become the antibiotics of last resort to treat CRAB despite their low therapeutic index due to potential nephrotoxicity. To address this unmet medical need, we aim to develop an effective combination agent comprising a polymyxin potentiator and an efficacious, mechanistically novel antibiotic, medinamycin (MedM). MedM is unaffected by clinically relevant modes of antibiotic resistance, exhibits low FOR and provides robust synergistic bactericidal activity against Ab, including colistin-resistant, MDR, and CRAB isolates, and is predicted to be a safe and effective antibiotic to permit lower effective doses of PMB, thereby reducing adverse effects. Aim 1 (Phase 1) Validate the feasibility of developing semisynthetic MedM analogs effective in combination with PMB and/or SPR741 against polymyxinR Ab. Improve MedM bioprocess to deliver >1 g for Aim 1 studies. Demonstrate chemical tractability. Develop the structure activity relationship (SAR) of new analogs using MOA, FOR, microbiological activity, and cytotoxicity assays. Demonstrate in vivo efficacy of a MedM analog + PMB against a PMBR Ab isolate in murine bacteremia infection model. Aim 2 (Phase 2) Complete bioprocess optimization and conduct a semisynthetic lead optimization with the goal of identifying MedM analogs with improved potency and/or drug like properties. Increase reliable production levels of MedM to >250 mg/L using 20L bioreactors, eventually producing 30 g of MedM. Using this material, prepare up to 150 semisynthetic analogs in an iterative fashion according to emerging SAR. Measure Ab MIC for all compounds, and for select compounds evaluate synergistic inhibitory concentration with potential polymyxin partners, in vitro tox and ADME, FOR, kill curves, PK and MIC90 to select polymyxin partner and analogs to advance to in vivo testing in Aim 3. Aim 3 (Phase 2) In vivo characterization of MedM analogs in combination with selected potentiator in relevant mouse models of Ab infection to identify lead series of combination product. Test efficacy of superior MedM analogs + polymyxin potentiator against a PMBR Ab clinical isolate in a mouse peritonitis infection model, followed by a deep thigh and neutropenic mouse lung infection model. In each study, demonstrate that a MedM analog provides statistically significant efficacy (P < 0.05) if combined with polymyxin at a sub-efficacious dose to identify lead MedM series for combination product. Dose fractionation studies will also be performed.
鲍曼不动杆菌(Ab)和相关菌种。引起严重的院内肺炎、伤口、血液和尿液 肠道感染,死亡率为25- 75%。多药耐药(MDR)抗体的出现 分离株使其难以用大多数标准护理抗生素治疗。碳青霉烯类已成为 然而,治疗Ab感染的首选疗法,现在超过50%的感染是碳青霉烯类耐药Ab (螃蟹)。因此,WHO和CDC将CRAB列为优先级-1关键和紧急 威胁病原体多粘菌素B(PMB)和粘菌素已成为治疗CRAB的最后手段, 由于潜在的肾毒性,其治疗指数较低。为了满足这一未得到满足的医疗需求,我们的目标是 开发一种有效的组合剂,包括多粘菌素增强剂和有效的、机械上的 新抗生素麦迪霉素(MedM)。MedM不受临床相关抗生素耐药性模式的影响, 表现出低FOR并提供针对Ab的强协同杀菌活性,包括粘菌素抗性, MDR和CRAB分离株,并被预测为安全有效的抗生素,以允许较低的有效剂量, PMB,从而减少不良影响。 目的1(第1阶段)验证开发有效的半合成MedM类似物的可行性, 与PMB和/或SPR 741组合对抗多粘菌素R Ab。改进MedM生物工艺, Aim 1研究。证明化学品的可处理性。开发新的结构活性关系(SAR) 使用MOA、FOR、微生物活性和细胞毒性测定来测定类似物。证明a的体内功效 MedM类似物+ PMB在鼠菌血症感染模型中针对PMBR Ab分离株。 目标2(第2阶段)完成生物工艺优化并进行半合成先导优化, 目的是鉴定具有改善的效力和/或药物样性质的MedM类似物。增加可靠性 使用20 L生物反应器将MedM生产水平提高至>250 mg/L,最终生产30 g MedM。使用此 材料,根据新兴的SAR以迭代方式制备多达150种半合成类似物。测量 所有化合物的Ab MIC和选定化合物的Ab MIC评价协同抑制浓度, 多粘菌素配偶体、体外毒性和ADME、FOR、杀伤曲线、PK和MIC 90,以选择多粘菌素配偶体, 类似物推进到目标3中的体内测试。 目的3(第2阶段)MedM类似物与所选增效剂组合的体内表征 相关小鼠Ab感染模型,以鉴定先导系列组合产品。测试功效 上级MedM类似物+多粘菌素增效剂在小鼠腹膜炎感染中对抗PMBR Ab临床分离株 模型,然后是深大腿和贫血小鼠肺部感染模型。在每项研究中,证明 如果与多粘菌素以亚有效浓度组合,MedM类似物提供统计学显著的功效(P < 0.05)。 剂量,以确定组合产品的主要MedM系列。还将进行剂量分次研究。

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 }}

Terry Roemer其他文献

Terry Roemer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('Terry Roemer', 18)}}的其他基金

Development of a novel broad spectrum antifungal therapeutic targeting Glycosylphosphatidylinositol (GPI) biosynthesis and cell wall biogenesis
开发一种针对糖基磷脂酰肌醇 (GPI) 生物合成和细胞壁生物合成的新型广谱抗真菌治疗药物
  • 批准号:
    10759723
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
Development of a mechanistically novel Gram-negative antibiotic targeting MsbA-mediated Lipopolysaccharide Biogenesis
开发一种机制新颖的革兰氏阴性抗生素,靶向 MsbA 介导的脂多糖生物发生
  • 批准号:
    10584170
  • 财政年份:
    2022
  • 资助金额:
    $ 30万
  • 项目类别:
Characterization of MsbA inhibitors as potential antibiotic leads to treat carbapenem-resistant Enterobacteriaceae (CRE)
MsbA 抑制剂作为潜在抗生素的特性可用于治疗耐碳青霉烯类肠杆菌 (CRE)
  • 批准号:
    10242174
  • 财政年份:
    2020
  • 资助金额:
    $ 30万
  • 项目类别:
Characterization of MsbA inhibitors as potential antibiotic leads to treat carbapenem-resistant Enterobacteriaceae (CRE)
MsbA 抑制剂作为潜在抗生素的特性可用于治疗耐碳青霉烯类肠杆菌 (CRE)
  • 批准号:
    9978345
  • 财政年份:
    2020
  • 资助金额:
    $ 30万
  • 项目类别:
Development of WecA-targeting immune potentiators to treat carbapenem-resistant Enterobacteriaceae (CRE) infections
开发 WecA 靶向免疫增强剂来治疗碳青霉烯类耐药肠杆菌 (CRE) 感染
  • 批准号:
    10415522
  • 财政年份:
    2019
  • 资助金额:
    $ 30万
  • 项目类别:
Development of WecA-targeting immune potentiators to treat carbapenem-resistant Enterobacteriaceae (CRE) infections
开发 WecA 靶向免疫增强剂来治疗碳青霉烯类耐药肠杆菌 (CRE) 感染
  • 批准号:
    10470327
  • 财政年份:
    2019
  • 资助金额:
    $ 30万
  • 项目类别:
Development of a novel agent to treat antimicrobial resistant Neisseria gonorrhoeae
开发治疗耐药性淋病奈瑟菌的新型药物
  • 批准号:
    9620389
  • 财政年份:
    2018
  • 资助金额:
    $ 30万
  • 项目类别:
Restoring Beta-lactam efficacy against methicillin-resistant Staphylococci
恢复 β-内酰胺对耐甲氧西林葡萄球菌的功效
  • 批准号:
    9814432
  • 财政年份:
    2018
  • 资助金额:
    $ 30万
  • 项目类别:
Development of a PO-administered beta-lactam-tarocin combination agent to treat methicillin susceptible and methicillin resistant Staphylococci
开发用于治疗甲氧西林敏感和甲氧西林耐药葡萄球菌的 PO 给药 β-内酰胺-塔罗辛组合药物
  • 批准号:
    10662488
  • 财政年份:
    2018
  • 资助金额:
    $ 30万
  • 项目类别:
Development of a novel agent to treat antimicrobial resistant Neisseria gonorrhoeae
开发治疗耐药性淋病奈瑟菌的新型药物
  • 批准号:
    9913150
  • 财政年份:
    2018
  • 资助金额:
    $ 30万
  • 项目类别:

相似国自然基金

共生细菌Acinetobacter soli来源精氨酸级联味觉受体NlGR21介导褐飞虱抗烯啶虫胺的分子机制
  • 批准号:
    JCZRYB202500693
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
细菌Acinetobacter sp.挥发物在瓜蚜蜜露调控龟纹瓢虫产卵定位中的作用研究
  • 批准号:
    32302339
  • 批准年份:
    2023
  • 资助金额:
    30.00 万元
  • 项目类别:
    青年科学基金项目
Acinetobacter sp. AS23菌株介导茶籽象耐受茶皂素毒性的分子机制解析
  • 批准号:
  • 批准年份:
    2022
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
  • 批准号:
    MR/Y008693/1
  • 财政年份:
    2024
  • 资助金额:
    $ 30万
  • 项目类别:
    Research Grant
Generative machine learning for narrow spectrum antibiotic discovery against Acinetobacter baumannii
生成机器学习用于发现针对鲍曼不动杆菌的窄谱抗生素
  • 批准号:
    477936
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
    Operating Grants
Conserved structural dynamics of outer-membrane channels in Acinetobacter baumannii as potential drug targets
鲍曼不动杆菌外膜通道的保守结构动力学作为潜在的药物靶点
  • 批准号:
    494854
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
    Operating Grants
Defining key players at the host-pathogen interface during Acinetobacter baumannii infection
定义鲍曼不动杆菌感染期间宿主-病原体界面的关键参与者
  • 批准号:
    488684
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
    Operating Grants
Study of clinically over-expressed and chimeric RND multidrug efflux pumps from Acinetobacter baumannii and Pseudomonas aeruginosa
鲍曼不动杆菌和铜绿假单胞菌临床过表达和嵌合 RND 多药外排泵的研究
  • 批准号:
    23K14346
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Biomimetic Macrophage Membrane-Coated Nanosponges: A Novel Therapeutic for Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii Hospital-Associated Pneumonia
仿生巨噬细胞膜包被的纳米海绵:一种治疗多重耐药铜绿假单胞菌和鲍曼不动杆菌医院相关肺炎的新疗法
  • 批准号:
    10674406
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
Using strain history to improve prediction of the evolution of antimicrobial resistance in Acinetobacter baumannii
利用菌株历史改进对鲍曼不动杆菌抗菌药物耐药性演变的预测
  • 批准号:
    10677362
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
Inhibitors of adaptive efflux mediated resistance in Acinetobacter baumannii
鲍曼不动杆菌适应性外排介导的耐药性抑制剂
  • 批准号:
    10625029
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
Creation of Active Substances from Deep-sea Actinomycetes to Disrupt Drug-Resistant Acinetobacter spp.
从深海放线菌中产生活性物质来破坏耐药不动杆菌属。
  • 批准号:
    22K19442
  • 财政年份:
    2022
  • 资助金额:
    $ 30万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
Identifying niche specific adaptations in Acinetobacter baumannii
鉴定鲍曼不动杆菌的生态位特异性适应
  • 批准号:
    10449699
  • 财政年份:
    2022
  • 资助金额:
    $ 30万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了