Antibiotic Tolerance and Therapeutic Failure in Diabetic Infections
Abstract
Compared to the general population, Veterans are two to three times more likely to have type 2 diabetes and associated health problems. An important health problem affecting Veterans and Americans with type 2 diabetes is the high rate of bacterial infections, particularly in the foot. This infection is called a diabetic foot infection and is most often caused by the bacterium Staphylococcus aureus. In diabetics, these infections are harder to treat and often result in antibiotic therapeutic failure that can lead to antibiotic resistance. When therapy fails, doctors usually utilize surgical treatments that can result in a complete or partial amputation of the foot. Each year, upwards of three thousand Veterans lose a foot to diabetic foot infections. This has an incalculable personal cost for each Veteran and a dramatic financial cost for the Veterans Health Administration (VHA). Understanding how to treat these infections more effectively has the potential to save lives, improve lifestyle and save the VHA significant financial resources. However, to better treat these infections, we must understand why they are so hard to treat in the first place. Additionally, long-term antibiotic treatment has been shown to impact the microbial community of the human gut and it is essential to understand how patient metabolism contributes to the stability of this community. Research has shown that a major cause of the high rates of infections and poor treatment outcomes among diabetics is a dysfunction of the immune system. Based on recent data and our previous work, we predict that in addition to the immune system, the elevated blood sugar of diabetics may also change how the infectious bacteria respond to antibiotics. We hypothesize that extra sugar in the patient may activate defensive responses in Staphylococcus aureus that protect them from antibiotics. In this work, we utilize a mouse model of diabetic foot infections to identify these predicted responses in Staphylococcus aureus and the total microbial community that makes up the microbiome. To do this, we will utilize two novel approaches that rely on modern genomic techniques. First, we will induce diabetic foot infections in mice using fifty thousand different Staphylococcus aureus mutants. Comparing mutants with and without a competitive advantage in this experiment will help us identify genes that help bacteria resist antibiotic therapy. This approach is called Tn-Seq. Next, using the same type of mice, we will study how diabetes and antibiotics impact the mouse microbiome, the total collection of good and bad bacteria found in the gut. To look at the microbiome, we will use a new approach that can tell us which bacteria are present in the gut and what they are doing in response to diabetes and antibiotics. This approach is called metatranscriptomics. Together these two approaches will help us identify why infections in diabetics often do not respond to therapy. In the long term, this information will help doctors select and design therapies that bypass newly identified protective responses used by bacteria. This work is particularly timely because more and more infections are becoming resistant to antibiotics, and we must counter this crisis by developing more effective therapies while mitigating negative impacts on the microbiome.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810198
Entities
People
- Peter Belenky
Organizations
- Brown University
- United States Army