New class of PBP inhibitors to address PBP2-mediated resistance in Neisseria gonorrhoeae
新型 PBP 抑制剂可解决淋病奈瑟菌 PBP2 介导的耐药性
基本信息
- 批准号:10228592
- 负责人:
- 金额:$ 144.11万
- 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:2019-09-05 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnti-Bacterial AgentsAnti-Infective AgentsAntibioticsAntigenic VariationAzithromycinBindingCefiximeCeftriaxoneCenters for Disease Control and Prevention (U.S.)Cephalosporin ResistanceCephalosporinsChemicalsChlamydia trachomatisClinicalClinical ResearchContractsCrystallizationCyclic GMPDevelopmentDisease NotificationDisease OutbreaksDoseDrug KineticsDrug TargetingEpidemiologyEscherichia coli InfectionsEvaluationEvolutionExhibitsFailureFemaleFormulationGoalsGonorrheaIn VitroIncidenceInfectionIntramuscularLeadLinkMaximum Tolerated DoseMediatingMedicalMethodsMicrobiologyModelingMosaicismMulti-Drug ResistanceMusNeisseria gonorrhoeaeOralOutpatientsPenicillin Binding Protein 2Penicillin-Binding ProteinsPharmaceutical PreparationsPharmacology StudyPlantsPreparationProcessPropertyRattusReportingResistanceRodentSafetySepticemiaSeriesServicesSouth CarolinaStructureTechnology TransferTestingTherapeuticToxicologyUniversitiesValidationVariantanalytical methodappropriate dosebactericidebasebeta-Lactamasebeta-Lactamsclinical candidateclinical developmentclinically relevantdesigndrug developmentdrug metabolismefficacy trialgenotoxicityglobal healthglobal health emergencyimprovedin vivoindexinginhibitor/antagonistlead optimizationmeetingsmethod developmentmouse modelnew combination therapiesnovelnovel therapeuticspharmacokinetics and pharmacodynamicspre-clinicalpreclinical developmentpressurepreventprogramsreproductive tractresistance frequencyresistance mechanismsynergismvaccine development
项目摘要
PROJECT SUMMARY
Multidrug resistant-gonorrhea is a serious global health threat. Penicillin Binding Protein-targeting β-lactams
have long been the front line therapeutic option for gonorrhea, but are now in serious jeopardy. Resistance to
the last remaining front line β-lactams, the extended spectrum cephalosporins, has steadily increased over the
past decades resulting in the CDC eliminating cefixime as a therapeutic option in 2012. Now only ceftriaxone
remains, but a series of resistant clinical isolates exhibiting PBP2-target based resistance have emerged in the
past decade, forecasting its imminent failure. As few clinical development candidates addressing MDR-
gonorrhea are in the drug development pipeline, and vaccine development is unlikely to be a solution due to high
antigenic variability in clinical isolates, there is an urgent need for new therapeutic options. A new chemical
series maintaining PBP target inhibition represents a promising strategy, enabling new combination therapies to
minimize further evolution of resistance. VenatoRx has identified a novel chemical series of reversible covalent
non-β-lactam Penicillin Binding Protein inhibitors impervious to the action of β-lactamases that are being
optimized to address altered PBP2 targets responsible for ESC-resistance in Neisseria gonorrhoeae. Significant
strides in microbiological activity have been achieved with the lead compound VNRX-6355 in MDR-gonorrhea
isolates including a mosaic PBP2-producing H041 clinical isolate. Improved binding to altered PBP2 variants by
VNRX-6355 has provided a >128-fold improvement in microbiological activity in H041 over initial hit compounds
in the series (shift in MIC from >512 mg/L to 4 mg/L) and is only 8-fold away from our MIC target to obtain an
MIC90 of ≤0.5 mg/L. These compounds are highly selective, rapidly bactericidal and efficacious in a murine
septicemia model of E. coli infection. The goal of this proposal is to select a potent preclinical candidate
addressing PBP2 target variants in ESC-resistant gonorrhea, confirm favorable PK properties for intramuscular
administration, select the first preclinical development candidate, perform preclinical IND-enabling studies and
file an IND with the US FDA. Ultimately this approach is intended to be a long term strategy to safeguard PBP-
targeting in gonorrhea treatment by preventing the expansion of β-lactamases in Neisseria gonorrhoeae that
would inevitably evolve from more effective targeting of PBP2 variants by current or newly optimized β-lactam-
based strategies.
项目总结
项目成果
期刊论文数量(0)
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Denis Marc Daigle其他文献
Denis Marc Daigle的其他文献
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{{ truncateString('Denis Marc Daigle', 18)}}的其他基金
New class of PBP inhibitors to address PBP2-mediated resistance in Neisseria gonorrhoeae
新型 PBP 抑制剂可解决淋病奈瑟菌 PBP2 介导的耐药性
- 批准号:
10686113 - 财政年份:2019
- 资助金额:
$ 144.11万 - 项目类别:
New class of PBP inhibitors to address PBP2-mediated resistance in Neisseria gonorrhoeae
新型 PBP 抑制剂可解决淋病奈瑟菌 PBP2 介导的耐药性
- 批准号:
10459332 - 财政年份:2019
- 资助金额:
$ 144.11万 - 项目类别:
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