Exploiting Host Polyamines for the Treatment of Skin and Wound Infections

利用宿主多胺治疗皮肤和伤口感染

基本信息

批准号：
8703874
负责人：
Anthony R. Richardson
金额：
$ 19.76万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703874
关键词：
Abscess Acetyltransferase Acinetobacter baumannii Adopted Affect Affinity Amoxicillin Amoxicillin-Potassium Clavulanate Combination Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antibiotics Arginine Bacteria Biological Assay Cations Cells Clavulanate Clinical Communities Diabetes Mellitus Disease Disease Outcome Enterococcus faecalis Enzymes Escherichia coli Event FDA approved Fluorescence Goals Growth Healed Homeostasis Homologous Gene Hospitals Human Immune response Infection Infectious Skin Diseases Inflammation Mediators Inflammatory Response Lead Leukocytes Mammalian Cell Mediating Methods Modeling Morbidity - disease rate Multi-Drug Resistance Mus Nature Outcome Phase Polyamine Catabolism Polyamines Postoperative Period Production Putrescine Resistance Resolution Series Signal Transduction Skin Skin Tissue Soft Tissue Infections Source Spermidine Spermidine/Spermine N1-Acetyltransferase Spermine Staphylococcus aureus Structure-Activity Relationship Testing Therapeutic Time Tissues Topical application Toxicity Tests Trauma Treatment Cost Treatment Protocols Vancomycin resistant enterococcus Wound Infection antimicrobial bactericide base cytotoxic diabetic diabetic patient effective therapy flexibility healing immunoregulation improved inhibitor/antagonist killings methicillin resistant Staphylococcus aureus mortality novel pathogen patient population public health relevance regenerative research study resistance mechanism resistant strain skin abscess skin lesion small molecule small molecule libraries success treatment strategy wound

项目摘要

DESCRIPTION (provided by applicant): Skin and soft tissue infections (SSTIs) and their associated complications represent a significant source of morbidity and mortality in the US, particularly when caused by multidrug-resistant (MDR) pathogens. The most common source of MDR associated SSTI is methicillin-resistant Staphylococcus aureus (MRSA). The host response during MRSA SSTIs involves two general phases: early on, a classical inflammatory response ensues including infiltrating leukocytes generating NO* in an attempt to sterilize the wound. Later, the host shifts into a wound-resolution and regenerative phase associated with anti-inflammatory mediators and growth promoting signals including the production of a class of compounds known as polyamines (i.e. putrescine, spermidine, and spermine). Both NO* and polyamines are synthesized from host arginine and the fate of arginine profoundly affects the outcomes of S. aureus infections. S. aureus is uniquely resistant to the cytotoxic effects of NO*, however polyamines are highly toxic to this pathogen. In fact, given the highly proliferative nature of a resolving skin lesion, polyamines become abundant enough during the resolution phase to directly kill MRSA. The only exceptions are isolates belonging to the emerging community-associated MRSA USA300 clones. These strains acquired a spermine/spermidine acetyltransferase (SpeG) that confers complete resistance to host polyamines and contributes to the remarkable success of these clones. Here we propose to develop novel inhibitors of bacterial SpeG-homologues and simultaneously optimize host polyamine levels in infected skin abscesses. This antimicrobial/anti-resistance approach would allow for the treatment of complicated MRSA SSTIs regardless of whether they are caused by SpeG-expressing USA300 strains. Interestingly, we found that eliminating SpeG-activity from a variety of wound-related MDR pathogens (e.g. Vancomycin-resistant Enterococcus faecalis, Acinetobacter baumannii, and E. coli) generally leads to polyamine sensitivity. Thus, this approach can be extended to treat wound infections caused by a many MDR bacteria. We outline our plan to develop a fluorescence-based assay to quantify USA300 SpeG activity that can be screened with a small molecule library targeted to define structure-activity relationships to previously identified low-affinity SpeG-inhibitors. Our goal is to find effective SpeG antagonists that can be safely applied topically to skin lesions in which we have optimized polyamine levels. Polyamine optimization can be accomplished by direct topical administration of spermine and/or spermidine simultaneously with FDA-approved agents that limit polyamine catabolism. Alternatively, we propose a series of experiments that test the feasibility of immunomodulation as a mechanism of polyamine optimization. Upon completing our aims, we will determine the safest and most effective mechanism of optimizing tissue polyamines during an SSTI and combine this with potent anti-SpeG compounds that will render a number of wound-related pathogens susceptible to elevated polyamines. We will ascertain whether this is an effective treatment on its own, or better serves to augment current treatment strategies given the documented synergy between polyamine- killing and traditional antibiotics. In the end, we hope to harness the anti-inflammatory nature of polyamines and at the same time exploit their antibacterial effects to improve disease outcomes of SSTIs caused by a variety of MDR pathogens.

描述（由申请人提供）：皮肤和软组织感染（SSTIS）及其相关并发症代表了美国的发病率和死亡率的重要来源，尤其是在由耐多药（MDR）病原体引起的时。 MDR相关的SSTI的最常见来源是耐甲氧西林金黄色葡萄球菌（MRSA）。 MRSA SSTIS期间的宿主反应涉及两个一般阶段：早期，随之而来的是经典的炎症反应，包括浸润白细胞产生NO*，以试图对伤口进行消毒。后来，宿主转变为与抗炎介质有关的伤口分辨率和再生阶段，并促进了促进信号，包括生产一种称为多胺的化合物（即prescine，prescine，permidine和obermine）。 NO*和多胺都是从宿主精氨酸合成的，精氨酸的命运深刻影响金黄色葡萄球菌感染的结果。金黄色葡萄球菌对NO*的细胞毒性作用具有独特的抗性，但是多胺对这种病原体具有剧毒。实际上，鉴于分辨皮肤病变的高度增殖性质，在分辨率阶段，多胺变得足够丰富，可以直接杀死MRSA。唯一的例外是属于新兴社区相关的MRSA USA300克隆的分离株。这些菌株获得了精子/精子乙酰基转移酶（SPEG），该酶赋予对宿主多胺的完全耐药性，并为这些克隆的显着成功做出了贡献。在这里，我们建议开发细菌SPEG-同源物的新型抑制剂，并同时优化受感染皮肤脓肿的宿主多胺水平。这种抗菌/抗耐药性方法将允许对复杂的MRSA SSTI进行治疗，而不管它们是否是由表达SPEG的USA300菌株引起的。有趣的是，我们发现从多种与伤口相关的MDR病原体（例如抗性万古霉素粪便，baumannii和大肠杆菌）消除SPEG活性通常会导致多胺敏感性。因此，可以扩展这种方法以治疗由许多MDR细菌引起的伤口感染。我们概述了开发基于荧光的测定法以量化USA300 SPEG活性的计划，该测定方法可以用旨在定义与先前鉴定的低亲和力SPEG抑制剂的结构活性关系的小分子库进行筛选。我们的目标是找到可以安全应用的有效的SPEG拮抗剂从局部进行皮肤病变，我们已经优化了多胺水平。多胺优化可以通过与FDA批准的剂量同时直接局部局部给予精子和/或精子来实现，从而限制了多胺分解代谢。另外，我们提出了一系列实验，以测试免疫调节作为多胺优化机制的可行性。完成目标后，我们将确定在SSTI期间优化组织多胺的最安全，最有效的机制，并将其与有效的抗SPEG化合物结合使用，该化合物将使许多与伤口相关的病原体易受升高多胺。我们将确定这是否是一种有效的治疗方法，或者更好地增加了当前的治疗策略，鉴于多胺杀伤和传统抗生素之间的协同作用。最后，我们希望利用多胺的抗炎性质，同时利用其抗菌作用来改善由多种MDR病原体引起的SSTI疾病结果。