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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.

摘要皮肤和软组织感染（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经常不能清除这些感染，导致慢性感染。感染并发展为更严重的感染，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。我们采用正常小鼠和糖尿病小鼠以及耐甲氧西林金黄色葡萄球菌的小鼠SSTI模型（MRSA）。我们观察到糖尿病患者的抗生素耐受性增加和自发性抗生素耐药（突变）。与感染MRSA的正常小鼠相比。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的过量葡萄糖环境改变细菌和宿主的代谢，从而驱动抗生素耐受性和抗性。在目标1中，我们将研究过量的葡萄糖如何引发S.金黄色葡萄球菌，导致酸化的感染微环境和增加的诱变，导致抗生素耐受性和耐药性。在aim 2中我们将研究糖尿病小鼠免疫系统的失能是如何诱导抗生素耐受和抗性S.金黄色葡萄球菌。在目标3中，我们将研究抗生素耐受性、耐药性和适应性，以确定导致高毒性、抗生素耐药菌株的突变进展，这些菌株可能高度有害给病人。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发展，并将进一步强调治疗和预防糖尿病的重要性，特别是作为率继续逐年上升。