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。抗微生物药物耐药性被广泛认为是最严重的公共卫生威胁之一
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)
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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:
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孕烷 X 受体 (PXR) 拮抗剂治疗非酒精性脂肪肝
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10016379 - 财政年份:2014
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PF4 小分子拮抗剂治疗和预防 HIT
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$ 29.16万 - 项目类别:
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9751604 - 财政年份:2014
- 资助金额:
$ 29.16万 - 项目类别:
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