Milk digestion inspires shuttles for antimicrobial drugs

As a growing number of disease-causing bacteria become resistant to antibiotics, scientists are scrambling to find new ways to prevent and treat infections. NCCR Bio-Inspired Materials researchers at the University of Fribourg have developed carriers that are just a few hundred of nanometers in size and can transport and release antimicrobial peptides — naturally occurring molecules that are increasingly being considered as useful alternatives to conventional antibiotics.

Because these nanocarriers can release antimicrobial peptides in response to changes in pH, they could be used to get the bacteria-killing molecules to wounds and infected tissues, which typically have abnormal pH values. The mini-shuttles could also be employed to combat stomach infections without affecting the beneficial bacteria that reside in the gut. “Because the drug-delivery system is active at the low pH values of the stomach but is inactive at the higher pH values of the intestine, it will only kill the bacteria in the stomach,” says NCCR Principal Investigator Stefan Salentinig, Professor of experimental physical chemistry at the University of Fribourg.

 Salentinig and his collaborators at the Swiss Federal Laboratories for Materials Science and Technology had previously shown that, as milk is digested in a lab-grown model of the human gut, it forms highly organized nanostructures. These structures could be important for transporting poorly water-soluble milk components through the digestive tract and delivering them across the gut lining. Inspired by these findings, Salentinig and his team set out to develop a drug delivery system that could protect antimicrobial peptides against breaking down in the body and release the bacteria-killing molecules in a controlled manner.

The researchers designed nanocarriers based on the assembly of a type of fatty molecule, known as DODAP, with the antimicrobial peptide LL-37, which is found in humans. At pH values of about 4.5, the fatty molecules that make up the nanocarriers form organized structures containing tiny water channels. Under these conditions, the antimicrobial peptide sits inside the nanocarriers, at the oil-water interface of the channels, the researchers found. At lower pH values, the fatty molecules form tiny sacs filled with water and the antimicrobial peptides. Because the peptides sit within the nanocarriers, either inside the water-filled sacs or at the oil-water interface of the channels, they are protected from degradation.

Things start to change as the pH becomes higher. When it reaches values of about 6, the fatty molecules turn into emulsion droplets, like those that form when oil and vinegar are whisked together into a salad dressing. Now, the antimicrobial peptides can be released and perform their antimicrobial function. The findings were published in the Journal of Colloid and Interface Science.

The structures that the nanocarriers form as the pH changes are similar to those observed during milk digestion, Salentinig says. “By changing the pH, we can blueprint the whole range of structures that you would find during milk digestion, and then we can use them to deliver antimicrobial peptides and switch on and off their activity,” he says.

Besides killing bacteria, the antimicrobial peptide LL-37 can favor cell proliferation, previous research has shown, thus promoting wound healing. Salentinig and his team developed a gel-like coating that contains the LL-37 antimicrobial peptide assembled with nanocarriers made of a food-grade fatty molecule called glycerol monooleate. In a study published in ACS Applied Bio Materials, the team tested the coating on two kind of disease-causing bacteria grown in a dish and found that it could kill both. The coating could find applications in wound pads to protect wounds and speed up healing, Salentinig says.

Reference: Gontsarik, M.; Yaghmur, A.; Salentinig, S. Dispersed liquid crystals as pH-adjustable antimicrobial peptide nanocarriers, J. Colloid Interface Sci., 2021, 853, 672-682.

Text by Giorgia Guglielmi