Small molecule can help fight antibiotic treatment failure

Since the 1940s, antibiotics have been our primary weapon against harmful bacterial infections. But some stubborn pathogens, like Staphylococcus aureus, can infect and hide within our own immune cells, making it extremely difficult for antibiotics to reach and eliminate them.

Brain Conlon, Ph.D., associate professor of microbiology and immunology at the UNC School of Medicine, and postdoctoral researcher Kuan-Yi Lu, Ph.D., thought outside the box.

Instead of focusing on more powerful antibiotics, researchers have explored ways to modify our own immune cells to help antibiotics work more effectively in the body. Conlon and Lu identified a small molecule that modifies the body’s immune cells, forcing them to “wake up” dormant bacteria inside and making them more vulnerable to antibiotic treatment.

As described in an article by Natural microbiologyThe introduction of the small molecule was effective in helping antibiotics better kill the bacteria that cause staph, tuberculosis and salmonella infections, three of the most common and serious infections worldwide.

“Twenty thousand people die each year from antibiotic-resistant staph infections, which means we need new ways to improve the effectiveness of antibiotics,” Conlon said. “For the first time, we have shown that it is possible to target the host to achieve better antibiotic outcomes.”

Researchers examined 5,000 small molecules to determine which were best at activating and killing dormant bacteria. Working with UNC’s Small Molecule Screening Core, they exposed each compound to immune cells infected with staphylococcal bacteria.

To see which compounds were most effective, the researchers used modified luminescent staph bacteria that glow a bright color when activated or “awakened,” much like a heat signature. The brighter the light, the more active the bacteria had become and the easier it would be for antibiotics to seek out and destroy hidden invaders.

One compound stood out. The researchers then introduced the compound into mouse models which, when administered in tandem with antibiotics, showed significant improvement in the antibiotics’ performance against Staphylococcus aureus and other bacteria hidden within immune cells, including Mycobacterium tuberculosis and Salmonella enterica.

“We found this to be a very good approach and an important proof of concept,” Conlon said. “S. aureus died much better when we used this small molecule, and we later found that it also worked against other intracellular pathogens.”

Conlon and Lu are now focused on identifying exactly how the molecule interacts with immune pathways, patenting the molecule for pharmacological use and determining whether similar strategies could help improve the treatment of other difficult-to-treat bacterial infections.