Diabetes and Antibiotic Treatment Failure

糖尿病和抗生素治疗失败

基本信息

批准号：
10564510
负责人：
Brian Patrick Conlon
金额：
$ 71.21万
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：
2022
资助国家：
美国
起止时间：
2022-11-14 至 2027-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564510
关键词：
Acetic Acids Acids Address Adult Affect Antibiotic Resistance Antibiotic Therapy Antibiotic susceptibility Antibiotics Automobile Driving Bacteremia Bacterial Antibiotic Resistance Bioinformatics Blood Glucose Carbon Cells Chronic Clinical Data Clinical Research Complication Consumption DNA Damage Data Defect Development Diabetes Mellitus Diabetic mouse Environment Evolution Frequencies Genetic Glucose Glycolysis Goals Growth Immune Immune response Immune system Immunosuppression In Vitro Individual Infection Inpatients Lactic acid Metabolic Diseases Metabolism Microbial Biofilms Modeling Mus Mutagenesis Mutation Nutrient Organism Osteomyelitis Patients Phagocytes Phenocopy Phenotype Population Positioning Attribute Predisposition Production Proliferating Relapse Research Personnel Resistance Respiratory Burst Role Sepsis Severities Sirolimus Skin Tissue Soft Tissue Infections Source Staphylococcus aureus Staphylococcus aureus infection Time Treatment Failure Treatment outcome Vancomycin Vancomycin Resistance Virulent antibiotic tolerance assault bactericide chronic infection diabetic diabetic patient experimental study fitness in vivo methicillin resistant Staphylococcus aureus mortality multidisciplinary pathogen pressure prevent resistant strain

项目摘要

Abstract Skin and soft tissue infection (SSTI) is a major complication in diabetic patients and Staphylococcus aureus is the most common causative organism. Antibiotics frequently fail to clear these infections, leading to chronic infection and progression to more severe infections such osteomyelitis and bacteremia. The reasons for the high rates of treatment failure in diabetic patients remain unclear. We employ a murine SSTI model with normal and diabetic mice and methicillin-resistant Staphylococcus aureus (MRSA). We observe increased antibiotic tolerance and spontaneous antibiotic resistance (mutation) in diabetic mice infected with MRSA, compared to the infected normal mice. We also observe a 10-fold increase in glucose concentrations in the diabetic infection environment. We hypothesize that excess glucose in the diabetic infection environment alters bacterial and host metabolism driving antibiotic tolerance and resistance. In aim 1 we will examine how excess glucose primes glycolysis in S. aureus, leading to acidification of the infection microenvironment and increased mutagenesis, resulting in antibiotic tolerance and resistance. In aim 2 we will examine how incapacitation of the immune system in diabetic mice may be inducing reservoirs of antibiotic tolerant and resistant S. aureus during infection. In aim 3, we will examine the in-host evolution of antibiotic tolerance, resistance, and fitness during sequential infection of diabetic mice to determine the progression of mutations that result in highly virulent, antibiotic resistant strains that are likely highly deleterious to the patient. Determining how blood glucose levels contribute to the development of antibiotic resistance will be an important development and will further emphasize the importance of treating and preventing diabetes, particularly as rates continue to rise annually.

抽象的皮肤和软组织感染（SSTI）是糖尿病患者的主要并发症，金黄色葡萄球菌是最常见的致病微生物。抗生素常常无法清除这些感染，从而导致慢性感染并进展为更严重的感染，例如骨髓炎和菌血症。高的原因糖尿病患者的治疗失败率仍不清楚。我们采用小鼠 SSTI 模型，其中包括正常小鼠和糖尿病小鼠以及耐甲氧西林金黄色葡萄球菌（耐甲氧西林金黄色葡萄球菌）。我们观察到糖尿病患者的抗生素耐受性增加和自发的抗生素耐药性（突变）感染 MRSA 的小鼠与感染的正常小鼠进行比较。我们还观察到葡萄糖增加了 10 倍糖尿病感染环境中的浓度。我们假设糖尿病感染中过量的葡萄糖环境改变细菌和宿主代谢，导致抗生素耐受性和耐药性。在目标 1 中，我们将研究过量的葡萄糖如何引发金黄色葡萄球菌中的糖酵解，从而导致感染微环境和诱变增加，导致抗生素耐受和耐药。目标2 我们将研究糖尿病小鼠免疫系统丧失能力如何诱导储存感染期间的抗生素耐受性和耐药性金黄色葡萄球菌。在目标 3 中，我们将研究宿主内的进化糖尿病小鼠连续感染期间的抗生素耐受性、抵抗力和适应性，以确定突变的进展导致产生高毒力、抗生素抗性菌株，这些菌株可能非常有害给病人。确定血糖水平如何促进抗生素耐药性的发展将是一个重要的问题的发展，并将进一步强调治疗和预防糖尿病的重要性，特别是随着发病率逐年持续上升。