Determining the value of PBP 7/8 as an antimicrobial target for XDR-A. baumannnii
确定 PBP 7/8 作为 XDR-A 抗菌靶点的价值。
基本信息
- 批准号:9888955
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-10-01 至 2023-09-30
- 项目状态:已结题
- 来源:
- 关键词:AbscessAcinetobacter baumanniiActive SitesAcuteAffectAnti-Bacterial AgentsAntimicrobial ResistanceAscitesAttentionBacillusBindingBiological AssayCarbapenemsCeftazidimeCellsCellular StructuresCharacteristicsComplementCytolysisDataDevelopmentDrug TargetingDrug resistanceESKAPE pathogensElementsEndopeptidasesEscherichia coliGenerationsGoalsGrowthHealthHealth Care CostsHealthcareHost DefenseHumanIn VitroIncidenceInfectionInsectaLaboratoriesLocationLong-Term CareMediatingMeropenemMethodsMicrobial BiofilmsMilitary PersonnelModelingMolecular WeightMonoclonal AntibodiesMonoclonal Antibody TherapyMorbidity - disease rateMuramidasePathogenicityPenicillin-Binding ProteinsPenicillinsPeptidoglycanPerformancePermeabilityPneumoniaPopulationPredispositionPrevention approachProcessProductionRattusReportingResearch PersonnelResistanceResistance developmentSalmonellaSerumSpecificityStructureSubcutaneous abscessTazobactamTestingTobramycinVeteransWorkantimicrobialantimicrobial drugassay developmentbactericidebasecapsulecostdrug developmentdrug resistant pathogenextensive drug resistancehigh throughput screeningin vivoinhibitor/antagonistinsightmolecular massmortalitynovel strategiespathogenperiplasmpreclinical studyresistant strainsmall moleculesmall molecule librariestooltraittransposon sequencing
项目摘要
Anticipated Impacts on Veterans Health Care. The incidence of infections due to highly resistant
Acinetobacter baumannii is increasing. True pan drug resistant (PDR) strains have been reported.
Unfortunately, the newly approved antimicrobials ceftolozane-tazobactam, ceftazidime-avibactam, and
meropenem/vaborbactam are poorly active against resistant A. baumannii. The need to identify new
antimicrobials active against A. baumannii is pressing.
Background. We have demonstrated that the A. baumannii low molecular mass (LMM) penicillin binding
protein 7/8 (PBP 7/8) is essential in vivo (i.e., required for bacterial survival in a host) in rat pneumonia and
subcutaneous abscess infection models, and is required for survival in human serum and ascites. Our initial
studies on PBP 7/8 were performed in an antimicrobial sensitive strain AB307-0294. These findings have
since been confirmed with the extensively drug resistant (XDR) strain HUMC1. Since our initial observation
other investigators, using INseq and Tn-seq, have shown that PBP 7/8 is needed for A. baumannii survival in
the Galleria mellonella insect infection model and serum respectively. PBP 7/8 has many characteristics that
support its potential as a high value drug target. However, based on studies in rich laboratory medium, LMM
PBPs including PBP 7/8 have been perceived to be non-essential. As a result, PBP 7/8 have received scant
attention as an antibacterial target and has not been considered for A. baumannii. However, our data
contradicts this paradigm and endorses the need for additional studies on PBP 7/8 in XDR A. baumannii.
Therefore, our objective is to validate PBP 7/8 as a drug target, delineate mechanisms that mediate its ex
vivo and in vivo essentiality, and to identify compounds that inactivate PBP 7/8.
Objectives and Methods. To achieve these objectives, studies on PBP 7/8 will be extended to include
additional XDR strains of A. baumannii to confirm our findings are generalizable (aim 1). Aim 1 also will also
explore mechanisms by which PBP 7/8 enables growth/survival of A. baumannii ex vivo and in vivo and
identify the innate host defense factors it protects against. Increasing data support the need to treat infections
due to XDR isolates with multiple agents, thereby increasing efficacy and protecting against the development
of resistance. Our demonstration that the loss of PBP 7/8 production increases susceptibility to complement
and lysozyme mediated bactericidal activity and changes cell structure supports the hypothesis that the
inability to produce PBP 7/8 affects permeability, a critical factor in the intrinsic antimicrobial resistance of A.
baumannii. Therefore, an additional goal of this proposal will be to assess the whether the loss of PBP 7/8
production enhances the activity of adjunctive therapy with antimicrobials and/or monoclonal antibodies
directed against the capsule (aim 2). Additional studies in aim 2 will assess whether the loss of PBP 7/8 affects
the production of other PBPs and ampC expression. These data will generate additional mechanistic insights
into the consequences of not being able to produce PBP 7/8. Lastly, aim 3 will begin the process of identifying
a “tool” compound that is active against PBP 7/8. A live wild-type XDR strain will be screened against a
chemical library to identify compounds directed against PBP 7/8 that possess bactericidal activity. Additional
orthogonal assays will establish specificity, determine their quality, and prioritize identified inhibitors for
downstream optimization and pre-clinical studies. Deliverables from this proposal will validate the paradigm
shift on the value of PBP 7/8 as an antimicrobial target and open an untapped venue for the development of
a new class of antimicrobial agents against this XDR pathogen.
对退伍军人医疗保健的预期影响。高耐药性药物导致的感染发生率
鲍曼不动杆菌在增加。已经报道了真正的泛耐药(PDR)菌株。
不幸的是,新批准的抗菌药物头孢洛扎-他唑巴坦、头孢他啶-阿维巴坦和
美罗培南/瓦硼巴坦对耐药A.鲍曼不动杆菌。需要确定新的
抗A.鲍曼尼正在施压。
背景我们证明了A.鲍曼不动杆菌低分子量青霉素结合
蛋白质7/8(PBP 7/8)在体内是必需的(即,细菌在宿主中存活所需),
皮下脓肿感染模型,并且是在人血清和腹水中存活所必需的。我们最初
在抗微生物敏感菌株AB 307 -0294中进行了对PBP 7/8的研究。这些发现
广泛耐药(XDR)菌株HUMC 1。从我们最初的观察
使用INseq和Tn-seq的其他研究者已经表明,A.鲍曼不动杆菌存活率
大蜡螟昆虫感染模型和血清。PBP 7/8具有许多特性,
支持其作为高价值药物靶点的潜力。然而,基于丰富的实验室培养基中的研究,LMM
包括PBP 7/8在内的PBP被认为是非必需的。因此,PBP 7/8收到的很少
注意作为抗菌靶标,并且尚未考虑用于A.鲍曼不动杆菌。然而,我们的数据
与这种范式相矛盾,并支持对XDR A中PBP 7/8进行额外研究的必要性。鲍曼不动杆菌。
因此,我们的目标是验证PBP 7/8作为药物靶点,阐明介导其表达的机制,
体内和体内的必要性,并确定化合物的PBP 7/8。
目标和方法。为达致这些目的,我们会把“警察局警诫计划7/8”的研究范围扩大,
另外的A. baumannii,以证实我们的研究结果是可推广的(目标1)。Aim 1还将
探索PBP 7/8使A.体外和体内鲍曼不动杆菌,
找出它所防御的宿主固有防御因子。越来越多的数据支持治疗感染的必要性
由于XDR分离株具有多种药物,从而提高了疗效并防止了
抗战我们证明,PBP 7/8生产的损失增加了对补体的敏感性,
和溶菌酶介导的杀菌活性和改变细胞结构支持了这一假设,
不能产生PBP 7/8影响渗透性,这是A.
鲍曼不动杆菌。因此,本提案的另一个目标是评估PBP 7/8的丢失是否
生产增强了抗微生物剂和/或单克隆抗体的连续治疗的活性
瞄准胶囊(目标2)。目标2中的其他研究将评估PBP 7/8的缺失是否影响
其他PBP的产生和ampC的表达。这些数据将产生额外的机械见解
无法生产PBP 7/8的后果。最后,目标3将开始确定
一种对PBP 7/8有活性的“工具”化合物。活的野生型XDR菌株将针对以下菌株进行筛选:
化学文库,以鉴定具有杀菌活性的针对PBP 7/8的化合物。额外
正交试验将建立特异性,确定其质量,并优先考虑已鉴定的抑制剂,
下游优化和临床前研究。本提案的可验证性将验证该范例
转变PBP 7/8作为抗菌靶标的价值,并为开发
针对这种XDR病原体的一类新的抗微生物剂。
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 }}
THOMAS A RUSSO其他文献
THOMAS A RUSSO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('THOMAS A RUSSO', 18)}}的其他基金
Identification of new or unrecognized virulence genes in hypervirulent Klebsiella pneumoniae and antivirulence genes in classical K. pneumoniae.
鉴定高毒力肺炎克雷伯菌中新的或未被识别的毒力基因和经典肺炎克雷伯菌中的抗毒力基因。
- 批准号:
10241918 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Identification of new or unrecognized virulence genes in hypervirulent Klebsiella pneumoniae and antivirulence genes in classical K. pneumoniae.
鉴定高毒力肺炎克雷伯菌中新的或未被识别的毒力基因和经典肺炎克雷伯菌中的抗毒力基因。
- 批准号:
9894988 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Determining the value of PBP 7/8 as an antimicrobial target for XDR-A. baumannnii
确定 PBP 7/8 作为 XDR-A 抗菌靶点的价值。
- 批准号:
10516081 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Determining the value of PBP 7/8 as an antimicrobial target for XDR-A. baumannnii
确定 PBP 7/8 作为 XDR-A 抗菌靶点的价值。
- 批准号:
10406232 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Determining the value of PBP 7/8 as an antimicrobial target for XDR-A. baumannnii
确定 PBP 7/8 作为 XDR-A 抗菌靶点的价值。
- 批准号:
10057228 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Development of a diagnostic test for hypervirulent Klebsiella pneumoniae
高毒力肺炎克雷伯菌诊断测试的开发
- 批准号:
9087528 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Analysis of A Baumannii Capsule as a Vaccine Candidate
鲍曼氏菌胶囊作为候选疫苗的分析
- 批准号:
8142286 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Analysis of A Baumannii Capsule as a Vaccine Candidate
鲍曼氏菌胶囊作为候选疫苗的分析
- 批准号:
8398944 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Analysis of A Baumannii Capsule as a Vaccine Candidate
鲍曼氏菌胶囊作为候选疫苗的分析
- 批准号:
8255320 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Identification of genes essential for survival of hypervirulent Kleb. pneumoniae
鉴定高毒力克雷布生存所必需的基因。
- 批准号:
8046754 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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:
-- - 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:
-- - 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:
-- - 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:
-- - 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:
-- - 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:
-- - 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:
-- - 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:
-- - 项目类别:
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:
-- - 项目类别:
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:
10596620 - 财政年份:2022
- 资助金额:
-- - 项目类别: