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Synergistic killing of bacterial pathogens by histones

组蛋白协同杀死细菌病原体

基本信息

批准号：
10457612
负责人：
Albert Siryaporn
金额：
$ 44.17万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-24 至 2022-07-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457612
关键词：
Address Antibiotic Resistance Antibiotics Attention Bacteria Bacterial Antibiotic Resistance Bacterial Infections Biology Biophysics Cells Cessation of life Chemicals Chronic Clinic Clinical Data Communities Complex Data Development Diabetes Mellitus Diabetic mouse Engineering FDA approved Gene Expression Goals Healthcare Histone H2A Histones Human Immune Immunology In Vitro Infection Infectious Skin Diseases Interdisciplinary Study Lipids Malignant Neoplasms Membrane Modeling Modernization Modification Molecular Morbidity - disease rate Multi-Drug Resistance Mus Obese Mice Organelles Outcome Pathogenesis Pathway interactions Patients Polymyxin B Pseudomonas aeruginosa Reporting Skin Soft Tissue Infections Standardization Staphylococcus aureus Structure Suspensions Systems Biology Testing Therapeutic Treatment Efficacy Work Wound Infection antimicrobial antimicrobial drug antimicrobial peptide antimicrobial peptide LL-37 bactericide cathelicidin chronic wound combat design diabetic diet-induced obesity drug resistant pathogen effective therapy efficacy testing experimental study extracellular health care settings histone modification human pathogen in vivo innovation insight methicillin resistant Staphylococcus aureus mortality mouse model neutrophil next generation non-diabetic non-healing wounds novel novel strategies novel therapeutics pathogen pathogenic bacteria pre-clinical resistant strain response scaffold skin wound soft tissue synergism uptake wound

项目摘要

Project Summary/Abstract The effective treatment of bacterial infections of skin, deep soft tissues and wounds continues to be a major unmet challenge in healthcare settings, especially among patients with chronic diabetes. Staphylococcus aureus and Pseudomonas aeruginosa are the most common bacteria that are isolated from chronic, non- healing wounds. Antibiotic resistance has arisen in these particular bacteria, causing these infections to become increasingly difficult to treat and giving rise to multi-drug resistant strains, including Methicillin-resistant Staphylococcus aureus (MRSA). The goal of the proposed work is to develop the next generation of therapeutics for which the design is inspired by a better mechanistic understanding of mammalian antimicrobial defense pathways. We focus our attention on the antimicrobial activities of neutrophil extracellular traps (NETs) and lipid droplet (LDs), which use histones to kill or suppress fungal and bacterial proliferation. The antimicrobial mechanism of histones has not been understood. The Siryaporn and Gross labs recently reported that the pairing of histones with an additional component found in NETs and LDs – the antimicrobial peptide (AMP) LL-37 (cathelicidin) – produces potent antimicrobial synergy. LL-37 forms pores in the bacterial membrane, which enable histones to enter the bacterium and interfere with gene expression. This has an irreversible bactericidal (killing) effect on bacteria. The work proposed here will exploit this discovery by identifying combinations of human histones and pore-forming antimicrobial agents that produce potent antimicrobial activity and synergy. The overall objective of the project is to better understand the mechanism of antimicrobial synergy between histones and pore- forming agents, and to harness it to create a class of new therapeutics for the treatment of skin infections and wounds. We will accomplish this objective by identifying combinations of human histones with LL-37 and other pore-forming antimicrobials that produce the greatest antimicrobial activities and synergies. We will test these against S. aureus, P. aeruginosa, and communities of skin bacteria in vitro (Aim 1). We will attempt to augment the antimicrobial activity by engineering in factors that impact histone function in NET and LDs, specifically chemical modification through citrullination and spatial localization to structures (Aim 2). To bring the strategy closer to the clinic, we will test the combinations of histones and pore-forming antimicrobials identified in Aims 1 and 2 in a standardized mouse skin infection model (Aim 3). To additionally address the unmet challenge of treating skin infection and wounds in diabetes patients, we will perform the tests in a diabetic mouse model. The results of this work will provide a mechanistic understanding of antimicrobial synergy and develop a strategy to combat the rise of antibiotic resistance. The results of the study could create a new class of antimicrobial therapeutics for the treatment of skin infections and wounds in diabetic and non-diabetic patients. This would represent a game-changer in the approach to antimicrobial treatments.

项目总结/摘要皮肤、深部软组织和伤口的细菌感染的有效治疗仍然是一个挑战。这是医疗保健环境中尚未解决的重大挑战，特别是在慢性糖尿病患者中。葡萄球菌金黄色葡萄球菌和铜绿假单胞菌是最常见的细菌，分离自慢性，非- 治愈伤口。抗生素耐药性已经出现在这些特定的细菌，导致这些感染，变得越来越难以治疗，并产生多重耐药菌株，包括耐甲氧西林菌株金黄色葡萄球菌（MRSA）。拟议工作的目标是开发下一代治疗方法，灵感来自于对哺乳动物抗菌防御途径的更好的机械理解。我们集中我们关注中性粒细胞胞外陷阱（NET）和脂滴（LD）的抗菌活性，使用组蛋白杀死或抑制真菌和细菌的增殖。组蛋白的抗菌机制不被理解。Siryaporn和Gross实验室最近报告说，组蛋白与一个 NET和LD中发现的其他成分-抗菌肽（AMP）LL-37（抗菌肽）- 产生有效的抗菌协同作用。LL-37在细菌膜上形成孔，使组蛋白能够进入细菌并干扰基因表达。这有一个不可逆的杀菌（杀死）效果，细菌这里提出的工作将通过鉴定人类组蛋白和产生有效的抗微生物活性和协同作用的成孔抗微生物剂。总体目标该项目的目的是更好地了解组蛋白和孔之间的抗菌协同作用的机制，形成剂，并利用它来创造一类用于治疗皮肤感染的新疗法，伤口我们将通过鉴定人组蛋白与LL-37和其他蛋白的组合来实现这一目标。产生最大抗菌活性和协同作用的成孔抗菌剂。我们将测试这些对于S.金黄色葡萄球菌、铜绿假单胞菌和体外皮肤细菌群落（目的1）。我们将尝试增加通过在NET和LD中影响组蛋白功能的因子中进行工程化，通过瓜氨酸的化学修饰和结构的空间定位（目标2）。把战略在更接近临床的情况下，我们将测试组蛋白和Aims中确定的成孔抗菌剂的组合 1和2在标准化小鼠皮肤感染模型中的作用（目的3）。为了进一步应对以下未得到满足的挑战，治疗糖尿病患者的皮肤感染和伤口，我们将在糖尿病小鼠模型中进行测试。这项工作的结果将提供一个抗菌协同作用的机制的理解和发展一项对抗抗生素耐药性上升的战略。这项研究的结果可能会创造一个新的类用于治疗糖尿病和非糖尿病患者的皮肤感染和伤口的抗微生物治疗剂。这将代表抗菌治疗方法的游戏规则改变者。