Diabetes and Antibiotic Treatment Failure

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 最常见的致病微生物。抗生素常常不能清除这些感染，导致慢性 感染并进展为更严重的感染，如骨髓炎和菌血症。高油价的原因 糖尿病患者的治疗失败率仍不清楚。 我们采用了正常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。我们还观察到血糖增加了10倍 糖尿病感染环境中的浓度。我们假设过多的葡萄糖在糖尿病感染中 环境改变了细菌和宿主的新陈代谢，导致了抗生素的耐受和耐药性。 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的糖酵解，导致金黄色葡萄球菌的酸化。 感染微环境和突变增加，导致抗生素耐药和耐药。在AIM 2 我们将研究糖尿病小鼠的免疫系统丧失能力是如何导致 感染期间对抗生素耐药和耐药的金黄色葡萄球菌。在目标3中，我们将研究宿主内的进化 在糖尿病小鼠连续感染期间的抗生素耐受性、耐药性和适合性以确定 导致高毒力、抗生素耐药性菌株的突变的进展，这些菌株可能是高度有害的 给病人的。 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 每年都在持续上升。

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.