Development of Broad-Spectrum Cyclic Amphiphilic Peptides against Multidrug-Resistant Bacteria
抗多重耐药细菌的广谱环状两亲肽的开发
基本信息
- 批准号:10685928
- 负责人:
- 金额:$ 29.66万
- 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:2022-08-18 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acinetobacter baumanniiAddressAdultAmino AcidsAnti-Bacterial AgentsAntibioticsAntimicrobial ResistanceArginineBacteriaBacterial Antibiotic ResistanceBacterial Drug ResistanceBiological AssayBody WeightC57BL/6 MouseCarbapenemsCell membraneCenters for Disease Control and Prevention (U.S.)CephalosporinsChargeCyclic PeptidesDaptomycinDataDevelopmentDoseDrug KineticsDrug resistanceESKAPE pathogensEnterobacterEnterococcus faeciumErythrocytesEscherichia coliEukaryotic CellExhibitsFeasibility StudiesGovernmentHalf-LifeHealth PersonnelHemolysisHistologyHumanHydrophobicityIn VitroInbred BALB C MiceInfectionIntravenousKlebsiella pneumoniaeLeadLegal patentLevaquinLibrariesLipidsMaximum Tolerated DoseMedicalMembraneMethicillinMicrobial BiofilmsModelingMonitorMulti-Drug ResistanceMultiple Bacterial Drug ResistanceMusMycobacterium tuberculosisPatientsPeptide LibraryPeptidesPeriodicityPersonsPhasePolymyxin BPseudomonas aeruginosaPublic HealthPyrazinamideReportingResistanceResistance developmentSafetyStaphylococcus aureusStaphylococcus aureus infectionStructure-Activity RelationshipTetracyclinesTherapeutic IndexTimeToxic effectTryptophanUnited KingdomVancomycinWorkamphiphilicityantimicrobialantimicrobial drugantimicrobial peptideantimicrobial resistant infectionassay developmentbiological systemsclinically relevantcohortcommercializationcytotoxicitydesigndosageeconomic impactefficacy studyexperimental studyimprovedin vivoindexinginsightisoniazidlead optimizationmethicillin resistant Staphylococcus aureusmortalitymouse modelmulti-drug resistant pathogennovelpathogenpathogenic bacteriapeptide amphiphilespeptide analogphase 2 studyresistant strainstructural determinants
项目摘要
ABSTRACT
The emergence of antibacterial resistance to common frontline antibiotics, such as methicillin, vancomycin, cephalosporins,
and carbapenem, have created a global public health challenge for millions of patients. It is therefore critical to discover and
commercialize new antimicrobial agents that can successfully neutralize multidrug-resistant bacteria (MDRB) with minimal
toxicity. The objective of this proposal is to develop unique first-in-class amphiphilic cyclic antimicrobial peptides (AMPs)
that are active against clinically relevant pathogens like Enterococcus faecium, Staphylococcus aureus, Klebsiella
pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE pathogens). We
propose to develop AMPs containing natural and/or unnatural hydrophobic and positively charged residues for their broad-
spectrum activity and efficacy against specific MDR pathogens, using in vitro and in vivo assays. We have discovered that
a cyclic amphipathic peptide [R4W4], which comprises tryptophan (W) and arginine (R) amino acids was effective against
diverse bacterial pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) (MIC = 2.7 µg/mL),
Pseudomonas aeruginosa (MIC = 42.8 µg/mL), Klebsiella pneumoniae (MIC = 16.0 µg/mL), and Escherichia coli (MIC =
16.0 µg/mL) and showed synergistic activity with tetracycline against MRSA, and isoniazid and pyrazinamide against
Mycobacterium tuberculosis. Based on this template, we generated a new library of peptides (>200) with enhanced
antimicrobial activities. For example, IFX-027, IFX-135, IFX-145, IFX-146, IFX-154, and IFX-301 showed MIC = 1.5-25
µg/mL against Gram+ve and Gram-ve bacteria. Several of the lead compounds demonstrated synergistic activity with
several other antibiotics with fractional inhibitory concentration (FIC) indices ranging from 0.3-0.5. Our lead peptides (IFX-
031, IFX-031-1, and IFX-111) also reduced biofilm formation by MRSA and P. aeruginosa. IFX-301 was found to be
nontoxic at a dose level of 50 mg/kg in mice, and all peptides were not toxic against human red blood cells (hRBC)
(HC50>500 μg/mL). In Aim 1, we will establish a structure-activity relationship (SAR) based on the six lead peptides to
obtain insights into the structural determinants responsible for the molecules’ selectivity towards bacterial pathogens. The
most potent compounds will be further evaluated for their stability, cytotoxicity, and development over time to antimicrobial
resistance. The proposed milestones for Aim 1 are to identify five lead peptide analogs with MIC ≤5 µg/mL and MIC ≤10
µg/mL respectively against Gram+ve and Gram-ve bacteria, and hRBC hemolysis of ≤5% at a concentration of 20 times
the MIC value. In Aim 2, we will evaluate the in vivo efficacy and toxicity, preliminary pharmacokinetics (e.g., Cmax, tmax,
t1/2), and efficacy of the 2-3 lead antimicrobial peptide analogs identified in Aim 1 on a murine infection model against four
pathogenic bacteria. At the successful completion of Phase I, the most potent compound with a large therapeutic index will
be advanced to Phase II studies and be the focus for an IND application.
摘要
对常见的一线抗生素,如甲氧西林、万古霉素、头孢菌素,
和碳青霉烯类抗生素,已经为数百万患者带来了全球公共卫生挑战。因此,至关重要的是要发现和
商业化新的抗菌剂,可以成功地中和多药耐药细菌(MDRB),
毒性本提案的目的是开发独特的一流的两亲性环状抗菌肽(AMP)
对临床相关病原体如屎肠球菌、金黄色葡萄球菌、克雷伯菌
肺炎杆菌、鲍曼不动杆菌、铜绿假单胞菌和肠杆菌属(ESKAPE病原体)。我们
建议开发含有天然和/或非天然疏水性和带正电荷残基的AMP,因为它们的宽-
使用体外和体内测定,对特定MDR病原体的谱活性和功效。我们发现
包含色氨酸(W)和精氨酸(R)氨基酸的环状两亲肽[R4 W 4]有效对抗
多种细菌病原体,如耐甲氧西林金黄色葡萄球菌(MRSA)(MIC = 2.7 µg/mL),
铜绿假单胞菌(MIC = 42.8 µg/mL)、肺炎克雷伯菌(MIC = 16.0 µg/mL)和大肠埃希菌(MIC =
16.0µg/mL),并与四环素对MRSA显示出协同活性,与异烟肼和吡嗪酰胺对MRSA显示出协同活性。
结核分枝杆菌。基于此模板,我们产生了一个新的肽库(>200),
抗菌活性。例如,IFX-027、IFX-135、IFX-145、IFX-146、IFX-154和IFX-301显示MIC = 1.5-25
μg/mL,对革兰氏阳性菌和革兰氏阴性菌。几种先导化合物显示出与以下化合物的协同活性:
其他几种抗生素的部分抑菌浓度(FIC)指数范围为0.3-0.5。我们的先导肽(IFX-
031、IFX-031-1和IFX-111)也减少MRSA和铜绿假单胞菌的生物膜形成。IFX-301被发现是
在小鼠中在50 mg/kg的剂量水平下是无毒的,并且所有肽对人红细胞(hRBC)都是无毒的。
(HC50>500 μg/mL)。在目标1中,我们将基于六个前导肽建立结构-活性关系(SAR),
深入了解负责分子对细菌病原体的选择性的结构决定因素。的
大多数有效的化合物将进一步评估其稳定性、细胞毒性和随着时间的推移对抗菌剂的发展。
阻力目标1的拟议里程碑是确定MIC ≤5 µg/mL和MIC ≤10的5种先导肽类似物
对革兰氏阳性菌和革兰氏阴性菌分别为μg/mL,20倍浓度hRBC溶血≤5%
MIC值。在目标2中,我们将评估体内功效和毒性、初步药代动力学(例如,Cmax,tmax,
t1/2),以及目标1中鉴定的2-3种前导抗微生物肽类似物对鼠感染模型抗四种
致病菌在第一阶段成功完成时,具有大治疗指数的最有效化合物将
进入II期研究,并成为IND申请的重点。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Membrane-Active Cyclic Amphiphilic Peptides: Broad-Spectrum Antibacterial Activity Alone and in Combination with Antibiotics.
- DOI:10.1021/acs.jmedchem.2c01469
- 发表时间:2022-12-08
- 期刊:
- 影响因子:7.3
- 作者:Mohammed EHM;Lohan S;Ghaffari T;Gupta S;Tiwari RK;Parang K
- 通讯作者:Parang K
Structure-Based Rational Design of Small α-Helical Peptides with Broad-Spectrum Activity against Multidrug-Resistant Pathogens.
- DOI:10.1021/acs.jmedchem.2c01708
- 发表时间:2023-01-12
- 期刊:
- 影响因子:7.3
- 作者:Lohan, Sandeep;Konshina, Anastasia G.;Efremov, Roman G.;Maslennikov, Innokentiy;Parang, Keykavous
- 通讯作者:Parang, Keykavous
{{
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 }}
Assad Kazeminy其他文献
Assad Kazeminy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('Assad Kazeminy', 18)}}的其他基金
Development of Broad-Spectrum Cyclic Amphiphilic Peptides against Multidrug-Resistant Bacteria
抗多重耐药细菌的广谱环状两亲肽的开发
- 批准号:
10481745 - 财政年份:2022
- 资助金额:
$ 29.66万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 29.66万 - 项目类别:
Research Grant