Antimicrobial resistance is one of the top 10 global public health threats, according to the World Health Organization, and scientists are scrambling to find new treatments for the deadliest drug-resistant infections.
Research by a University of Maryland scientist in collaboration with the National Institute of Allergy and Infectious Diseases shows that reducing the virulence of drug-resistant infections, rather than trying to completely kill the bacteria, could provide an alternative treatment approach.
Their study showed how two types of proteins allow MRSA, or methicillin-resistant Staphylococcus aureus (MRSA), to release toxins that cause disease in humans. The study suggests that treatments targeting these two proteins could inactivate MRSA, making it less lethal and potentially harmless. This approach will also reduce the risk of developing antibiotic resistance.
The article will be published February 13, 2023 in Proceedings. of National Academy of Science reports that similar mechanisms may exist in other bacteria, indicating the possibility of a new approach to treating other bacterial infections.
“We were looking for an alternative way to fight MRSA,” said Seth Dickey, assistant professor of veterinary medicine at the University of Maryland and lead author of the study. “We were interested in understanding how bacteria cause disease in order to see.” if we could interfere directly with the virulence factors(s). “virulence) produced by bacteria. If we could disarm them, we might not have to worry about them evading antimicrobial agents.”
Antimicrobial resistance occurs when drug treatment kills some, but not all, bacterial cells. And the remaining bacteria tend to have some natural resistance, so if they have a chance to repopulate, the next infection will be stronger against antibiotics. This unintentional selective breeding has led to the emergence of supermicrobes such as MRSA and multidrug-resistant tuberculosis.
An approach to treating infections that makes them less dangerous without killing them may preclude the possibility of such selective breeding. In MRSA, these efforts are hampered by the fact that the bacteria produce several types of toxins in abundance. Understanding and blocking each mechanism is a major challenge. So Dickey and his colleagues decided to look not at how cells produce toxins, but at how they are released to their host.
Previous work by Dickey and other groups has shown that two proteins act as gateways to transport toxin molecules across the bacterial cell membrane to the outside. But it is not clear why there are two types of transporter proteins and how they work. Without this understanding, scientists cannot develop treatments that prevent the release of toxins.
To understand the mechanism involved, Dickey and his team genetically engineered each type of transporter and observed how MRSA cells release toxins.
They found that one of the carrier proteins picks up hydrophilic or water-attracting toxins that float in the cell’s cytoplasm and transports them across the cell membrane. When this transporter was absent, hydrophilic toxins continued to accumulate inside MRSA cells, where they were harmless to both MRSA and any potential host.
When the team removed the second carrier protein, which is hydrophobic or water-repellent, toxins accumulated in the cell.
This is important because these toxins tend to move out of the watery cytoplasm on their own and settle in the oilier cell membrane. This is where MRSA toxins damage host cells and MRSA cells.
So, without a second carrier protein, MRSA cells are damaged by hydrophobic toxins. This suggests that future treatments targeting one vector may reduce virulence, and treatments targeting a second vector may also reduce virulence as well as provide antibiotic effects.