UMD-led Study Suggests New Strategy to Fight Deadly Bacterial Infections

Deadly infections that shrug off all the antibiotics doctors can throw at them represent one of the top 10 global public health threats, according to the World Health Organization, and scientists have been scrambling to find new tools to fight growing antimicrobial resistance. Now, research led by a University of Maryland scientist in collaboration with the National Institute of Allergy and Infectious Diseases suggests that reducing the severity of drug-resistant infections—rather than trying to kill bacteria outright—may offer an effective alternative approach.

Their study, published yesterday in the Proceedings of the National Academy of Science, revealed how two proteins enable the dangerous and widespread MRSA (methicillin-resistant Staphylococcus aureus) bacterium to secrete the toxins that make people sick.

Therapies targeting these two proteins instead of the whole organism could disable the so-called superbug that plagues medical facilities and schools, making it less deadly and possibly even harmless, the researchers reported. Such an approach would also reduce the risk of antibiotic resistance.

“We were interested in understanding how the bacterium causes disease to see if we could interfere directly with the virulence factors that the bug produces,” said Seth Dickey, an assistant professor in the UMD Department of Veterinary Medicine and lead author of the study. “If we can disarm it, then we may not have to worry about it evading antimicrobial agents.”

Antimicrobial resistance develops when a drug treatment knocks down some, but not all of the bacterial cells. The bacteria that remain have some natural resistance, so if they have a chance to recolonize, the next infection will be stronger in the face of antibiotics. This unintentional selective breeding has led to super-bugs like MRSA and multi-drug resistant tuberculosis.

An approach to treating infection that makes it less harmful without killing it could eliminate the potential for such selective breeding. In MRSA, that effort has been hindered by the fact that the bacterium makes several types of toxins in abundance. Understanding each mechanism and shutting it down are tremendously challenging. So, Dickey and his colleagues decided not to look at how the cells produce toxins, but how they secrete those toxins into their host.

Previous work by Dickey and other teams found that two proteins serve as ferries to transport the molecules of toxin across the bacterial cell membrane to the outside environment. But it was unclear why there were two transporter proteins and how they functioned. Without this understanding, scientists cannot develop therapies to prevent the secretion of toxins.

The study reveals how the two proteins work together to move two kinds of toxins across the cell membrane, demonstrating that when the proteins were removed, toxins built up inside MRSA cells where they could not affect the host. Removing one of the proteins even resulted in the bacteria being damaged by their own poisons.

The findings have implications beyond MRSA. When the researchers looked at the genomes of a variety of other bacteria, they found that many have genes for producing a system similar to the one they found in MRSA, pointing to the potential for a new approach to fighting a range of infections.