Development of FosA Inhibitors to Potentiate Fosfomycin Activity in Gram-Negative Pathogens
开发 FosA 抑制剂以增强磷霉素对革兰氏阴性病原体的活性
基本信息
- 批准号:10684118
- 负责人:
- 金额:$ 29.16万
- 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:2022-08-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Abdominal InfectionAcuteAdjuvantAffinityAntibiotic TherapyAntibioticsAntimicrobial ResistanceBacteremiaBacteriaBacterial InfectionsBacterial PneumoniaBindingBiologicalBiological AssayCarbonChemicalsClinicalDataDevelopmentDrug IndustryDrug KineticsDrug TargetingDrug resistanceEnsureEnterobacterEpoxy CompoundsEscherichia coliEvaluationExcretory functionFormulationFosfomycinFutureGenesGlutathioneGlutathione S-TransferaseGoalsGram-Negative BacteriaHomologous GeneHospitalsHumanIndustry StandardInfectionIntra-abdominalIntravenousKlebsiella pneumoniaeLeadLegal patentLung infectionsMeasuresMediatingMetabolismMulti-Drug ResistanceNational Institute of Allergy and Infectious DiseaseOralPathway interactionsPenetrationPharmaceutical ChemistryPhasePneumoniaPositioning AttributePredispositionProcessProductionPropertyProteinsPseudomonas aeruginosaPseudomonas aeruginosa pneumoniaPublic HealthRecordsResearchResistanceResistance developmentRoentgen RaysRouteSafetyScientistSmall Business Technology Transfer ResearchStructureTherapeutic UsesToxic effectTransferaseUniversitiesUrinary tract infectionVentilatorabsorptionanalogantimicrobialclinically relevantcombatdesigndimerdrug developmentdrug discoveryexperiencein vitro Assayin vitro activityinhibitorinsightiterative designlead optimizationnovelnovel strategiesnucleophilic additionpathogenpharmacophorepre-clinicalresistant Klebsiella pneumoniaeresistant strainscale upsmall molecule inhibitorsuccess
项目摘要
Summary. Antimicrobial resistance is widely recognized as one of the most significant public health threats of
the century. Many bacterial infections have become difficult to treat due to antimicrobial resistance, and there is
an urgent need to develop new strategies to combat these resistant pathogens. One such strategy is to reposition
older antibiotics that have long-track records of safety in human. Fosfomycin (FOM) is an etablished antibiotic
which inactivates UDP-N-acetylglucosamine enolpyruvyl transferase in both Gram-positive and -negative
pathogens. Currently, FOM is exclusively used as an oral formulation for the treatment of urinary tract infections
given its excellent activity against Escherichia coli. However, an intravenous FOM formulation is used elsewhere,
and is currently pending FDA approval in U.S. Furthermore, an ongoing NIAID-sponsored trial (NCT03910673)
is exploring whether intravenous FOM can effectively treat lung infections, such as hospital-acquired and
ventilator-associated bacterial pneumonia. FosA is a dimeric K+- and Mn2+-dependent glutathione S-transferase
that catalyzes the nucleophilic addition of glutathione to carbon-1 in the epoxide ring of FOM, rendering the
antibiotic inactive. E. coli lacks intrinsic chromosomal fosA, thus explaining its acute susceptibility to FOM.
However, fosA homologues are chromosomally encoded by many Gram-negative species including
Pseudomonas aeruginosa and Klebsiella pneumoniae. Our prior research has clearly demonstrated that this
intrinsic production of FosA confers FOM resistance, and that inactivation of FosA provides a novel approach to
increase the sensitivity of carbepenem resistant Gram-negative pathogens to FOM, thus highlighting a novel
pathway to expand the use of FOM to a wide range of Gram-negative species. Importantly, and central to this
application, we recently identified and patented a first-in-class, competitive small molecule inhibitor of FosA
(ANY1) which potentiates FOM activity against Gram-negative pathogens that harbor the fosA gene. Using
insights from the ANY1-FosA X-ray crystal structure, we have designed and prepared an analog that has ~10X
greater potency, showing that further SAR development is possible. The aims in this proposal are (1) medicinal
chemistry optimization of FosA inhibitors, (2) evaluation and optimization of ADME properties, and (3) biological
evaluation against a broad panel of XDR Gram-negative clinical isolates. We anticipate that such a combination
could be used to treat invasive infections including bacteremia, pneumonia, intra-abdominal infections and
complicated UTIs caused by Gram-negative bacteria that harbor fosA (e.g., K. pneumoniae, Enterobacter spp.,
P. aeruginosa), including extremely drug resistant strains. In this Phase I proposal, we will identify and evaluate
FosA inhibitors based on ANY1 by combining the pharmaceutical and medicinal chemistry expertise of the
scientists at the Fox Chase Chemical Diversity Center, Inc. (FCCDC) with the expertise and experience of the
Sluis-Cremer lab at the University of Pittsburg in the experimental aspects of FosA inhibition and antibiotic
therapy.
总结。抗菌素耐药性被广泛认为是最严重的公共卫生威胁之一
世纪之交。许多细菌感染由于抗菌素耐药性而变得难以治疗,而且
迫切需要开发新的战略来对抗这些耐药病原体。其中一种策略是重新定位
对人类安全有长期记录的较老的抗生素。磷霉素(FOM)是一种公认的抗生素
该药可灭活革兰氏阳性和阴性患者的UDP-N-乙酰氨基葡萄糖烯醇式丙酮基转移酶
病原体。目前,FOM仅用作治疗尿路感染的口服制剂。
鉴于其对大肠杆菌具有极好的抗菌活性。然而,静脉注射FOM配方在其他地方使用,
目前正在美国等待FDA的批准。此外,正在进行的NIAID赞助的试验(NCT03910673)
正在探索静脉注射FOM是否可以有效治疗肺部感染,如医院获得性和
呼吸机相关性细菌性肺炎。FOSA是一种依赖K+和Mn2+的二聚体谷胱甘肽S转移酶
催化谷胱甘肽与FOM环氧环上的碳-1的亲核加成反应,使
抗生素无效。大肠埃希氏菌缺乏固有的染色体FOSA,因此对FOM敏感。
然而,FOSA同源物是由许多革兰氏阴性物种在染色体上编码的,包括
铜绿假单胞菌和肺炎克雷伯菌。我们之前的研究已经清楚地证明了这一点
FOSA的内在产生赋予了FOM抗性,而FOSA的失活提供了一种新的方法来
增加耐碳青霉烯的革兰氏阴性病原菌对FOM的敏感性,从而突出了一种新的
将FOM的使用扩大到广泛的革兰氏阴性菌的途径。重要的是,这一点也是核心
我们最近发现并申请了一种一流的、具有竞争力的FOSA小分子抑制剂的专利
(Any1),它增强了FOM对含有FOSA基因的革兰氏阴性病原体的活性。vbl.使用
从Any1-FOSA X射线晶体结构的洞察,我们设计并制备了一种~10倍的模拟
更大的潜力,表明特区的进一步发展是可能的。这项建议的目的是(1)医疗
FOSA抑制剂的化学优化,(2)ADME性能的评价和优化,以及(3)生物
对广泛的XDR革兰氏阴性临床分离株的评估。我们预计这样的组合
可用于治疗侵袭性感染,包括菌血症、肺炎、腹内感染和
由含有FOSA的革兰氏阴性细菌(如肺炎克雷伯菌、肠杆菌属、
铜绿假单胞菌),包括极耐药菌株。在此第一阶段提案中,我们将确定和评估
基于Any1的FOSA抑制剂,结合了
福克斯·蔡斯化学多样性中心(FCCDC)的科学家拥有
匹兹堡大学的Sluis-Cremer实验室在FOSA抑制和抗生素的实验方面
心理治疗。
项目成果
期刊论文数量(0)
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Jay Edward Wrobel其他文献
Jay Edward Wrobel的其他文献
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{{ truncateString('Jay Edward Wrobel', 18)}}的其他基金
Development of FosA Inhibitors to Potentiate Fosfomycin Activity in Gram-Negative Pathogens
开发 FosA 抑制剂以增强磷霉素对革兰氏阴性病原体的活性
- 批准号:
10545935 - 财政年份:2022
- 资助金额:
$ 29.16万 - 项目类别:
INHIBITORS OF THE PHD2 ZINC FINGER TO TREAT ANEMIA
PHD2 锌指抑制剂治疗贫血
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9345190 - 财政年份:2017
- 资助金额:
$ 29.16万 - 项目类别:
Pregnane X Receptor (PXR) Antagonists for Non-Alcoholic Fatty Liver Disease
孕烷 X 受体 (PXR) 拮抗剂治疗非酒精性脂肪肝
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8905004 - 财政年份:2015
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Small Molecule Antagonists of PF4 for the Treatment and Prevention of HIT
PF4 小分子拮抗剂治疗和预防 HIT
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10016379 - 财政年份:2014
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$ 29.16万 - 项目类别:
Small Molecule Antagonists of PF4 for the Treatment and Prevention of HIT
PF4 小分子拮抗剂治疗和预防 HIT
- 批准号:
10179443 - 财政年份:2014
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Small Molecule Antagonists of PF4 for the Treatment and Prevention of HIT
PF4 小分子拮抗剂治疗和预防 HIT
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9751604 - 财政年份:2014
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$ 29.16万 - 项目类别:
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