Determinants and Mechanisms of Efficacy of Peptide Antibiotics as Novel Sepsis Therapy
肽抗生素作为新型脓毒症治疗功效的决定因素和机制
基本信息
- 批准号:10454970
- 负责人:
- 金额:$ 36.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAmino AcidsAnimal ModelAnti-Bacterial AgentsAntibiotic ResistanceAntibioticsAntimicrobial Cationic PeptidesAntisepsisAttenuatedBacteremiaBacteriaBacterial InfectionsBacterial ModelBasic ScienceBiophysicsBlood CirculationCationsClinical ResearchColistinCombined AntibioticsCommunicable DiseasesComplexDataDevelopmentDivalent CationsDoseDrug KineticsDrug toxicityESKAPE pathogensEndotoxinsEngineeringFatality rateFrequenciesFunctional disorderGoldGrantHumanHydrophobicityImipenemImmune responseIn VitroInfectionInflammationInnate Immune ResponseInvestigationKlebsiella pneumoniaeLeadLethal Dose 50LibrariesLifeMammalian CellMaximum Tolerated DoseMeasuresMediatingMedicalModelingMolecularMorbidity - disease rateMulti-Drug ResistanceMultiple Bacterial Drug ResistanceMusOperative Surgical ProceduresOrganPatientsPatternPeptide AntibioticsPeptide LibraryPeptidesPharmaceutical PreparationsPlant RootsPlasmaPropertyPseudomonas aeruginosaPublic HealthRegimenResearchResearch PersonnelResistanceRoleSafetySalineSepsisSepticemiaSerial PassageSeriesSideSignal TransductionStructureSystemic Inflammatory Response SyndromeSystemic infectionTLR4 geneTestingTherapeuticTherapeutic IndexTherapeutic UsesTopical applicationToxic effectToxicologyTranslational ResearchTreatment FactorTreatment FailureUnited Statesantimicrobialantimicrobial peptidearginylvalineattenuationbacterial resistancebactericidebasecathelicidin antimicrobial peptidececal ligation punctureclinical developmentdesigndosageefficacy evaluationhydrophilicityin vivoindexinginfectious disease treatmentinnovationlead candidatemortalitymouse modelnovelnovel antibiotic classnovel strategiespathogenpolymicrobial sepsispreclinical studypublic health relevancerational designstandard of caresuccesstherapeutically effective
项目摘要
Project summary/Abstract
The premise of the proposal is that cationic antimicrobial peptides (AMPs) can be designed to enhance systemic
efficacy for sepsis treatment based on the unique properties to kill bacteria regardless of multidrug resistance
(MDR) as well as to attenuate inflammation mediated by endotoxin stimulation of toll like receptor (TLR) 4. This
will be accomplished using a series of rationally engineered libraries of novel peptide antibiotics (PAX) to
establish the distinction between structural determinants of antimicrobial potency and those of host toxicity.
Sepsis or SIRS (systemic inflammatory response syndrome) is defined as a “life-threatening organ dysfunction
caused by a dysregulated host response to infection.” Sepsis-related fatality rate is approximately 30% annually,
which may reach up to 50% in more severe cases. The development of multiple classes of antibiotics toward the
mid-20th century initially led to a sharp decline in sepsis-related mortality. However, persistent sepsis morbidity
and mortality, even with the use of effective antibiotics, is indicative of heightened immune responses and MDR.
The increased frequency of MDR bacteria has created an urgent need for the development of novel classes of
antibiotics with new antimicrobial mechanisms. In addition, sepsis has a complex pathophysiology that makes it
difficult to treat. By mitigating stimulation of inflammation via TLR4 signaling and eliminating the causative agent
(bacteria), AMPs has the potential to eradicate the problem by its root. Over the past decade we have developed
novel strategies to design and characterize cationic AMPs for treatment of infections associated with MDR
bacteria based on de novo engineered cationic antimicrobial peptides (eCAPs). The use of Trp substitution on
the hydrophobic side results in two lead peptides (WLBU2 and WR12) that retain broad-spectrum activity in
saline, acidic pH, and human plasma, indicating the specific roles of different amino acids in AMP function. Both
eCAPs were effective against 89-92% of a diverse panel of ESKAPE (MDR) pathogens compared to activity
against only 50% of these strains displayed by both the human AMP LL37 and colistin. WLBU2 also displays
systemic efficacy in a P. aeruginosa septicemia model, which dispels the notion that AMPs ought to be used
only topically to be effective. A single systemic dose of WLBU2 protects mice injected with an otherwise lethal
inoculum of P. aeruginosa. However, an important concern is a narrow therapeutic index [TI = maximum tolerated
dose (MTD)/minimum therapeutic dose (mTd)]) of 3-5 (mTd of 3-4mg/kg and MTD of 12-15mg/kg) of WLBU2,
which will be addressed in this proposed research. We hypothesize that AMPs can be designed for application
to sepsis treatment based on a rational framework for structure-function correlations by elucidating the unique
contributions of the cationic and hydrophobic contents to antibacterial selectivity, endotoxin neutralization, and
host toxicity. To address this hypothesis, we will examine efficacy in murine models of bacterial sepsis and cecal
ligation puncture-induced polymicrobial sepsis. This basic and translational research will result in the final
selection of a single effective drug for advanced pre-clinical and clinical studies for sepsis treatment.
项目概要/摘要
该提案的前提是,阳离子抗菌肽(AMP)可以被设计为增强全身性
基于杀灭细菌的独特特性,无论多重耐药性如何,
(MDR)以及减轻由Toll样受体(TLR)4的内毒素刺激介导的炎症。这
将使用一系列合理工程化的新型肽抗生素(PAX)文库来完成,
确定抗菌效力的结构决定因素与宿主毒性的结构决定因素之间的区别。
脓毒症或全身炎症反应综合征(SIRS)被定义为“危及生命的器官功能障碍
是由宿主对感染的反应失调引起的”脓毒症相关的死亡率每年约为30%,
在更严重的情况下可能高达50%。多类抗生素的发展,
世纪中期,最初导致败血症相关死亡率急剧下降。然而,持续的脓毒症发病率
和死亡率,即使使用有效的抗生素,也表明免疫应答和MDR增强。
MDR细菌频率的增加已经迫切需要开发新型的耐药药物。
具有新抗菌机制的抗生素。此外,脓毒症具有复杂的病理生理学,
通过TLR 4信号传导减轻炎症刺激并消除病原体,
(细菌),抗菌肽有可能从根本上根除问题。在过去的十年里,我们发展了
设计和表征用于治疗MDR相关感染的阳离子AMP的新策略
细菌的基础上从头工程阳离子抗菌肽(eCAP)。Trp取代在
疏水侧产生两个前导肽(WLBU 2和WR 12),其在
生理盐水、酸性pH和人血浆,表明不同氨基酸在AMP功能中的特定作用。两
与活性相比,eCAP对89-92%的多种ESKAPE(MDR)病原体有效
针对人AMP LL 37和粘菌素两者所展示的这些菌株中的仅50%。WLBU 2还显示
在铜绿假单胞菌败血症模型中的全身有效性,这消除了应该使用AMP的概念
只有局部才有效。单次全身剂量的WLBU 2保护注射了其他致死性毒素的小鼠。
铜绿假单胞菌接种物。然而,一个重要的问题是狭窄的治疗指数[TI =最大耐受
剂量(MTD)/最小治疗剂量(mTd)])3-5(mTd为3- 4 mg/kg,MTD为12- 15 mg/kg)的WLBU 2,
这将在这项研究中得到解决。我们假设AMP可以被设计用于
脓毒症治疗的基础上的结构-功能相关性的合理框架,通过阐明独特的
阳离子和疏水含量对抗菌选择性、内毒素中和和
宿主毒性为了解决这一假设,我们将在细菌性脓毒症和盲肠炎的小鼠模型中检查疗效。
结扎穿刺引起的多微生物败血症。这种基础和转化研究将导致最终的
选择单一有效药物用于脓毒症治疗的高级临床前和临床研究。
项目成果
期刊论文数量(3)
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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Berthony Deslouches其他文献
Berthony Deslouches的其他文献
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{{ truncateString('Berthony Deslouches', 18)}}的其他基金
Structural determinants of activity and mechanism of cationic peptide antibiotic activity against colistin-resistant bacteria
阳离子肽抗生素对粘菌素耐药菌活性的结构决定因素和机制
- 批准号:
10733264 - 财政年份:2023
- 资助金额:
$ 36.45万 - 项目类别:
Determinants and Mechanisms of Efficacy of Peptide Antibiotics as Novel Sepsis Therapy
肽抗生素作为新型脓毒症治疗功效的决定因素和机制
- 批准号:
9750739 - 财政年份:2018
- 资助金额:
$ 36.45万 - 项目类别:
Determinants and Mechanisms of Efficacy of Peptide Antibiotics as Novel Sepsis Therapy
肽抗生素作为新型脓毒症治疗功效的决定因素和机制
- 批准号:
10218207 - 财政年份:2018
- 资助金额:
$ 36.45万 - 项目类别:
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