Antibiotics are powerful, fast-acting drugs that were developed to fight bacterial infections. In recent years, however, their reliability has diminished as antibiotic-resistant bacteria continue to evolve and spread. Staphylococcus aureus is one of the main causes of infections and deaths associated with antibiotic resistance. It is also the most common bacterial infection in people with diabetes mellitus, a chronic condition that affects blood sugar control and reduces the body’s ability to fight infection.
Microbiologists Brian Conlon, PhD, and Lance Thurlow, PhD, of the UNC School of Medicine have shown that people with diabetes are also more likely to develop antibiotic-resistant Staphylococcus aureus strains. Their findings, published in Science Advances, highlight how the microbial environment of diabetics breeds resistant mutations, while also pointing to ways to combat antibiotic resistance in this patient population. “We have found that antibiotic resistance emerges much faster in diabetes models than in non-diabetic disease models,” said Conlon, associate professor in the Department of Microbiology and Immunology. This interaction between bacteria and diabetes could be a major factor in the rapid development and spread of antibiotic resistance.
Study With Antibiotics in a Diabetic Mouse Model
Diabetes impairs the body’s ability to control a type of sugar called glucose, which often leads to excess glucose accumulating in the bloodstream. Staphylococcus aureus feeds on these high sugar levels, allowing it to multiply faster. The bacteria can also grow without consequences, as diabetes also impairs the immune system’s ability to destroy cells and control infections. As the number of bacteria in a diabetic infection increases, so does the likelihood of resistance. Random mutations occur and some develop resistance to external stressors such as antibiotics. Once a resistant mutant is present in a diabetic infection, it quickly takes over the population and uses the excess glucose for its rapid growth.
“Staphylococcus aureus is uniquely suited to take advantage of this diabetic environment,” said Thurlow, assistant professor of microbiology and immunology with joint appointments at the UNC School of Medicine and the Adams School of Dentistry. “Once this resistant mutation occurs, there is an excess of glucose and the immune system is unable to clear the mutant, so it takes over the entire bacterial population within a few days.”
Conlon, an expert on antibiotic treatment failure, and Thurlow, an expert on staphylococcal pathogenesis in diabetes, have long been interested in comparing the effectiveness of antibiotics in a model with and without diabetes. Using their connections within the Department of Microbiology and Immunology, the researchers brought their labs together to conduct a study of antibiotics in a diabetic mouse model of S. aureus infection.
Bacteria Develop Resistance to the Drug
First, the team prepared a mouse model with a bacterial infection of the skin and soft tissue. The mouse models were divided into two groups: One half received a compound that selectively kills cells in the pancreas and makes them diabetic, while the other half did not receive the compound. The researchers then infected both diabetic and non-diabetic models with S. aureus and treated them with rifampicin, an antibiotic to which resistance develops very quickly. After five days of infection, it was time to observe the results.
The researchers quickly realized that the rifampicin had virtually no effect on the diabetic models. So they took some samples for examination. They were shocked to find that the bacteria had developed resistance to rifampicin, and the infection contained over a hundred million rifampicin-resistant bacteria. In the non-diabetic models, there were no rifampicin-resistant bacteria. And even more surprising was that the mutation had taken over the entire infection in just four days. Next, diabetic and non-diabetic models were inoculated with Staphylococcus aureus as before, but this time with a known number of rifampicin-resistant bacteria. Again, these bacteria quickly took over the diabetic infection, but remained only as a subpopulation in non-diabetic models after four days of rifampicin treatment.
Investigation of the Development of Resistance in Humans (With and Without Diabetes)
The new findings have raised many questions. However, the researchers are certain that the development of antibiotic resistance in people with diabetes could become problematic for the population as a whole. Antibiotic-resistant strains of bacteria spread from person to person in the same way as other bacteria and viruses – through the air, on doorknobs and through the food we eat. Preventing this type of infection is therefore a top priority.
So what can be done to prevent it? Conlon and Thurlow’s labs have shown that lowering blood glucose levels in diabetes models (by administering insulin) deprives bacteria of their fuel, keeps their numbers in check and reduces the likelihood of antibiotic-resistant mutations occurring. Their findings suggest that controlling blood sugar levels through insulin administration could be the key to preventing antibiotic resistance. When the researchers administered insulin to their mice, they were able to normalize their blood sugar levels and there was no rapid proliferation of resistant bacteria.
Now the researchers are expanding their efforts to study the development of resistance in humans (with and without diabetes) and other antibiotic-resistant bacteria of interest, including Enterococcus faecalis, Pseudomonas aeruginosa and Streptococcus pyogenes. Recognizing the major role that the host plays in the development of antibiotic resistance, the experts plan to conduct similar studies in patients undergoing chemotherapy and recent transplant recipients to see if these populations are also susceptible to antibiotic-resistant infections.