Antimicrobial Peptides and their Synthetic Mimics - Investigating the Mechanism o

抗菌肽及其合成模拟物 - 研究其作用机制

基本信息

批准号：
8078139
负责人：
David Gidalevitz
金额：
$ 28.65万
依托单位：
ILLINOIS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8078139
关键词：
Advanced Development Air Anti-Bacterial Agents Antibiotics Antimicrobial Resistance Antiviral Agents Bacteria Binding Biological Assay Biological Availability Biomimetics California Cell Wall Cell membrane Cell surface Cells Chemistry Chicago Cholesterol Circular Dichroism Clinical Research Collaborations Communicable Diseases Comparative Study Cytolysis Cytoskeleton Data Development Disease Drug usage Engineering Erythrocytes Event Fluorescence Funding Gram-Negative Bacteria Gram-Positive Bacteria Human Illinois Immune Immune system Incidence Institutes Knowledge Laboratories Left Lipid Bilayers Lipids Liquid substance Los Angeles Lytic Mediating Membrane Membrane Lipids Membrane Proteins Methodology Methods Microscopy Molecular Mono-S Multi-Drug Resistance Mutation N-substituted Glycines Nature Neutrons Oligonucleotides Peptide Antibiotics Peptide Hydrolases Peptides Peptoids Pharmaceutical Preparations Pharmacologic Substance Phosphatidyl glycerol Phosphatidylglycerols Physics Plasma Cells Polymers Property Protozoa Reporting Request for Proposals Research Research Personnel Research Project Grants Resistance Resolution Roentgen Rays Role Science Solid Solutions Staging Structure Structure-Activity Relationship Surface Synchrotrons System Techniques Technology Therapeutic Universities Vesicle Viral Virus Water Work X ray diffraction analysis X-Ray Diffraction analog antimicrobial antimicrobial drug antimicrobial peptide aqueous bacterial resistance base design drug resistant bacteria fungus immunogenicity infrared spectroscopy interest microbicide mimicry monolayer novel novel strategies pathogenic bacteria receptor self assembly solid state viral envelope lipids

项目摘要

DESCRIPTION (provided by applicant): Antimicrobial peptides (AMP) form a first line of defense of the innate immune system and have a broad spectrum of microbicidal activity against a wide range of Gram-negative and Gram-positive bacteria, fungi, protozoa, and even enveloped viruses. Recently they became a matter of increasing interest because of their excellent potential in treating diseases which cannot be cured by conventional antibiotics due to antimicrobial resistance. AMPs either induce membrane damage that is a lethal event for target bacteria or bind to several targets in the cytoplasmic region of the bacteria. All the evidence indicates that the action of the AMPs does not involve stereospecific protein-receptor recognition, since the interactions of AMPs with their targets are generally considered to be nonspecific. Therefore, the character of AMP interaction with bacterial cell wall lipids, viral envelope, or native plasma cell membrane lipids largely determine their lytic potential. As part of our study, novel planar biomimetic membranes, both at air-water and solid-liquid interface will be developed. This will allow use of highly sensitive structural experimental techniques, which cannot be employed with vesicle systems nor with real cells. Furthermore, in addition to AMP we also plan to investigate membrane interactions of their synthetic peptoid mimics (ampetoids), which have an advantage of being protease-resistant, while showing high potency and selectivity as antimicrobial agents. In this highly interdisciplinary proposal we plan to use cutting edge synchrotron X-ray scattering techniques, which together with AFM and epifluorescence studies will yield near atomic resolution of peptide-lipid interaction. These data will be used to advance the understanding of AMP and ampetoids mode of action which can be used to develop rational design strategies for AMPs and antimicrobial peptide mimics to advance development of highly potent drugs that are effective even against multidrug resistant bacteria and viruses. Specific aims of this project are: (1) Examine the modes of interaction of ampetoids and natural AMPs with lipid monolayers representing an outer leaflet of red blood cell membranes and surface layer of bacterial cell wall using synchrotron grazing incidence X-ray diffraction, X-ray reflectivity, epifluorescence microscopy, and AFM used in complementary manner. (2) Design novel fluid bilayer membranes at the air-water interface, use them to examine the interaction of AMPs and ampetoids with both leaflets of bilayer membrane. (3) Design novel cholesterol tethered bilayer lipid membranes (tBLM) with cytoskeleton component. Examine mechanism of AMPs and ampetoids interaction with these tBLMs and elucidate role of cytoskeleton in their interactions. The broader impact of the proposed research is to advance development of novel antibiotic and antiviral drugs that will be immune to bacterial and viral mutations. Antimicrobial peptides and their synthetic mimics have enormous potential with regard to bacterial resistance because they interact not only with specific membrane protein receptors, but also with the lipid matrix of cell membranes, whose lipid composition is highly unlikely to change as a result of bacterial mutation. Better understanding of antimicrobial peptides and peptoids mode of action on molecular level could enhance the design and development of potent alternatives to the conventional antibiotics and antiviral drugs used today.

描述（由申请人提供）：抗菌肽 (AMP) 形成先天免疫系统的第一道防线，对多种革兰氏阴性和革兰氏阳性细菌、真菌、原生动物和细菌具有广谱杀菌活性。甚至有包膜病毒。最近，它们越来越受到人们的关注，因为它们在治疗由于抗菌素耐药性而无法用传统抗生素治愈的疾病方面具有巨大的潜力。 AMP 要么诱导膜损伤（对目标细菌而言是致命事件），要么与细菌细胞质区域中的多个目标结合。所有证据都表明 AMP 的作用不涉及立体特异性蛋白质受体识别，因为 AMP 与其靶标的相互作用通常被认为是非特异性的。因此，AMP 与细菌细胞壁脂质、病毒包膜或天然浆细胞膜脂质相互作用的特征在很大程度上决定了它们的裂解潜力。作为我们研究的一部分，我们将开发空气-水和固-液界面的新型平面仿生膜。这将允许使用高度敏感的结构实验技术，该技术不能用于囊泡系统或真实细胞。此外，除了 AMP 之外，我们还计划研究其合成拟肽模拟物（ampetoids）的膜相互作用，其具有耐蛋白酶的优点，同时显示出作为抗菌剂的高效力和选择性。在这个高度跨学科的提案中，我们计划使用尖端的同步加速器 X 射线散射技术，该技术与 AFM 和落射荧光研究一起将产生接近原子分辨率的肽-脂质相互作用。这些数据将用于增进对 AMP 和 ampetoids 作用模式的理解，可用于开发 AMP 和抗菌肽模拟物的合理设计策略，以促进甚至对多重耐药细菌和病毒也有效的高效药物的开发。该项目的具体目标是：（1）使用同步加速器掠入射 X 射线衍射、X-射线衍射，检查 ampetoids 和天然 AMP 与代表红细胞膜外层和细菌细胞壁表面层的脂质单层的相互作用模式。射线反射率、落射荧光显微镜和 AFM 以互补方式使用。 (2)在空气-水界面设计新型流体双层膜，用它们研究AMPs和ampetoids与双层膜两个小叶的相互作用。 (3)设计具有细胞骨架成分的新型胆固醇栓系双层脂膜(tBLM)。检查 AMP 和 ampetoids 与这些 tBLM 相互作用的机制，并阐明细胞骨架在它们相互作用中的作用。拟议研究的更广泛影响是促进新型抗生素和抗病毒药物的开发，这些药物将对细菌和病毒突变免疫。抗菌肽及其合成模拟物在细菌耐药性方面具有巨大潜力，因为它们不仅与特定的膜蛋白受体相互作用，而且与细胞膜的脂质基质相互作用，而细胞膜的脂质成分极不可能因细菌突变而改变。更好地了解抗菌肽和类肽在分子水平上的作用模式可以促进当今使用的传统抗生素和抗病毒药物的有效替代品的设计和开发。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A comparative study on the interactions of SMAP-29 with lipid monolayers.

DOI：
10.1016/j.bbamem.2009.09.017
发表时间：
2010-05
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
影响因子：
3.4
作者：
Neville, Frances;Ivankin, Andrey;Konovalov, Oleg;Gidalevitz, David
通讯作者：
Gidalevitz, David

Antibacterial properties and mode of action of a short acyl-lysyl oligomer.

短酰基-赖氨酰低聚物的抗菌特性和作用方式。

DOI：
10.1128/aac.00010-09
发表时间：
2009
期刊：
Antimicrobial agents and chemotherapy
影响因子：
4.9
作者：
Zaknoon,Fadia;Sarig,Hadar;Rotem,Shahar;Livne,Liran;Ivankin,Andrey;Gidalevitz,David;Mor,Amram
通讯作者：
Mor,Amram

Mechanism of membrane perturbation by the HIV-1 gp41 membrane-proximal external region and its modulation by cholesterol.

DOI：
10.1016/j.bbamem.2012.06.002
发表时间：
2012-11
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Ivankin A;Apellániz B;Gidalevitz D;Nieva JL
通讯作者：
Nieva JL

Role of the conformational rigidity in the design of biomimetic antimicrobial compounds.

DOI：
10.1002/anie.201003104
发表时间：
2010-11-02
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Ivankin, Andrey;Livne, Liran;Mor, Amram;Caputo, Gregory A.;DeGrado, William F.;Meron, Mati;Lin, Binhua;Gidalevitz, David
通讯作者：
Gidalevitz, David

Cyclization Improves Membrane Permeation by Antimicrobial Peptoids.

DOI：
10.1021/acs.langmuir.6b03477
发表时间：
2016-12-06
期刊：
LANGMUIR
影响因子：
3.9
作者：
Andreev, Konstantin;Martynowycz, Michael W.;Ivankin, Andrey;Huang, Mia L.;Kuzmenko, Ivan;Meron, Mati;Lin, Binhua;Kirshenbaum, Kent;Gidalevitz, David
通讯作者：
Gidalevitz, David