Diabetes can drive the evolution of antibiotic resistance

Antibiotics are powerful and fast-acting drugs that treat bacterial infections. However, overuse and misuse has caused widespread antimicrobial resistance which continues to evolve and spread.

Staphylococcus aureus (Staph) – the most common human pathogen – is a leading cause of antibiotic resistance associated with infection and death. It is also the most prevalent bacterial infection among those with diabetes mellitus (T2DM), a chronic condition that primarily affects blood sugar control but also reduces the body’s ability to fight infections.

Microbiologists Brian Conlon, PhD, and Lance Thurlow, PhD, at the University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina, have demonstrated that people with T2DM are also more likely to develop antibiotic-resistant strains of Staph. The results of the study, published February 2025 in Science Advances, show how the diabetic microbial environment produces resistant mutations, while hinting at ways antibiotic resistance can be tackled in this patient population.

“We found that antibiotic resistance emerges much more rapidly in diabetic models than in non-diabetic models of disease,” said Conlon, associate professor at the UNC Department of Microbiology and Immunology.

“This interplay between bacteria and T2DM could be a major driver of the rapid evolution and spread of antibiotic resistance that we are seeing.”

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T2DM limits the body’s ability to control blood glucose, allowing for excess glucose to build up in the patient’s bloodstream. Staph can reproduce more rapidly in this high sugar environment, also developing without fewer immunological obstacles, as T2DM also impairs the host’s immune system’s ability to control infection.

As the numbers of bacteria increase in a diabetic infection, so does the likelihood of resistance. Rapid replication means that mutations will appear randomly and some bacterium will build up resistance to external stressors, such as antibiotics.

Once a resistant mutant strain is present in a diabetic infection, it rapidly takes over the population, using the excess glucose to drive further rapid development of the colony.

“Staph is highly adapted to take advantage of the diabetic environment,” said Thurlow, assistant professor of microbiology and immunology.

“Once that resistant mutation happens, you have [all the] excess glucose and you don't have the [well-functioning] immune system to clear the mutant [strain] and it takes over the entire bacterial population in a matter of days.”

Conlon, an expert on antibiotic treatment failure, and Thurlow, an expert on Staph pathogenesis in diabetes, have long been interested in comparing the effectiveness of antibiotics in a model with and without diabetes. The researchers brought their labs in the UNC Department of Microbiology and Immunology together to perform a study with antibiotics in a diabetic mouse model of Staph infection.

First, the team prepared a mouse model with bacterial infection in the skin and soft tissue. The mouse models were divided into two groups: one half was given a compound that selectively kills cells in the pancreas, rendering them diabetic, and the other half was not given the compound. Researchers then infected both diabetic and non-diabetic models with Staph and treated them with rifampicin – an antibiotic which treats mycobacterial and gram-positive bacterial infections – but is also known to be vulnerable to resistance evolving rapidly. The bacteria were left to develop for five days.

It was noted that the rifampicin had practically no effect in diabetic models. Investigative samples showed that the bacteria had evolved to become resistant to rifampicin, with the infection harbouring more than a hundred million rifampicin resistant bacteria. It was a shocking finding. By contrast, in the non-diabetic models there were no rifampicin resistant bacteria found.

They next exposed the diabetic and non-diabetic models to the Staph infection, as before, but this time supplemented with a known number of rifampicin resistant bacteria. Again, these bacteria rapidly took over the diabetic infection but remained as only a sub-population in non-diabetic models after four days rifampicin treatment.

The findings have left Conlon and Thurlow with many questions; but the implication of the results that antibiotic resistance can develop so quickly in people with T2DM is troubling for healthcare professionals and policy makers who are working to combat the worsening of antimicrobial resistance.

The researchers also showed that by reducing blood sugar levels in diabetic models through the administration of insulin had the effect of depriving bacteria of the glucose-rich environment that supported rapid replication and mutation. The findings suggest that controlling blood sugar through administering insulin could be a key tool in limiting antibiotic resistance.

“[Antimicrobial] resistance and its spread are not only associated with the prescription of drugs, but also the health status of those that are taking the antibiotics,” said Conlon. “Controlling blood glucose then becomes really important. When we gave our mice insulin, we were able to bring their blood sugar back to normal and we didn't get this rapid proliferation of resistant bacteria.”

Now, Conlon and Thurlow are expanding their efforts to study the evolution of resistance in humans – with and without diabetes – and other antibiotic-resistant bacteria of interest, including Enterococcus faecalis, Pseudomonas aeruginosa, and Streptococcus pyogenes.

Recognising how large a role the host plays a role in the evolution of antibiotic resistance; the study team aims to perform similar studies in patients undergoing chemotherapy and also recent transplant recipients to see if those populations are also susceptible to antibiotic resistant infections.