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.

项目摘要/摘要有效治疗皮肤，深软组织和伤口的细菌感染是一种医疗保健环境中的重大挑战，尤其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，是从慢性，非 - 康复胜利。这些特定细菌已经引起了抗生素耐药性，导致这些感染变得越来越难以治疗并引起多药耐药菌株，包括耐甲氧西林金黄色葡萄球菌（MRSA）。拟议工作的目的是开发设计的下一代治疗剂灵感来自对哺乳动物抗菌防御途径的更好理解。我们集中精力注意中性粒细胞外陷阱（网）和脂质液滴（LDS）的抗菌活性，这些活性使用组蛋白杀死或抑制真菌和细菌增殖。组蛋白的抗菌机制具有没有被理解。 Siryaporn和Gross Labs最近报告说，组蛋白与在网和LDS中发现的其他成分 - 抗菌胡椒（AMP）LL-37（cathelicidin） - 产生潜在的抗菌协同作用。 LL-37在细菌膜中形成毛孔，使组蛋白成为输入细菌并干扰基因表达。这具有不可逆转的细菌（杀死）对细菌。这里提出的工作将通过识别人类组蛋白和的组合来利用这一发现产生潜在的抗菌活性和协同作用的孔形成抗菌剂。总体目标该项目的一个是更好地了解组蛋白和孔隙蛋白之间抗菌协同作用的机制形成剂，并利用它创建一类新疗法，以治疗皮肤感染和伤口。我们将通过确定人类组蛋白与LL-37和其他其他的组合来实现这一目标产生最大抗菌活性和协同作用的孔形成抗菌剂。我们将测试这些反对金黄色葡萄球菌，铜绿假单胞菌和体外皮肤细菌群落（AIM 1）。我们将尝试增强通过工程化在影响NET和LD的组蛋白功能的因素中，抗菌活性，特别是化学修饰通过柠檬酸化和空间定位到结构（AIM 2）。带来策略靠近诊所，我们将测试AIM中鉴定出的组蛋白和形成孔的抗菌剂的组合标准化小鼠皮肤感染模型中的1和2（AIM 3）。另外解决未满足的挑战为了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对抗菌协同作用的机械理解，并发展打击抗生素耐药性崛起的策略。该研究的结果可能会创建一个新的类用于治疗糖尿病和非糖尿病患者皮肤感染和伤口的抗菌疗法。这将代表改变抗菌治疗方法的游戏改变者。