Superbug's Weak Spot Could Be Its Protein Factory
Researchers in the US have spotted a weakness in the internal machinery of a superbug that could offer new targets for drugs. They believe the key lies with the molecular mechanisms that antibiotic-resistant bacteria use to manufacture life-essential proteins, without which they soon perish.
Biologists Gloria Culver and Keith Connolly came to this conclusion while studying bacterial ribosomes at the University of Rochester in New York. (Connolly has since moved to Harvard Medical School in Boston). They write about their findings in the March print issue of Molecular Microbiology. Superbugs "Superbugs" is the term given to bacteria that cause infections that have become virtually impossible to treat, even deadly, because misuse of antibiotics has led to strains that are highly resistant to current drugs, in some cases, even those of last resort.
For their study, Culver and Connolly thought they might spot a weakness, an "Achilles heel", by examining the internal workings of a particularly nasty superbug, E. coli.
E. coli is normally found in the gut, where it lives quite harmlessly in the abudant garden of intestinal flora. But some strains, if they get into the bloodstream can cause food poisoning, and if they happen to be ones that are also difficult to treat, the infection becomes very serious and potentially life-threatening. Ribosomes in E. coli Don't Work If Proteins RbfA and KsgA Not In Balance Ribosomes are the protein-producing factories in the cells of all living organisms, with different organisms using different types of ribosome to make proteins that are unique to their particular life-forms.
Culver says in a statement that they decided to study ribosomes because "cells and organisms can't live if they don't make proteins, and they can't make proteins if their ribosomes aren't functioning properly".
When they looked at ribosomes in E. coli, Culver and Connolly noticed that two proteins already present in the bacterium's cell, RbfA and KsgA, have to be in balance with each other, or the ribosome machinery won't function.
If there is an imbalance in the two proteins with respect to each other, the ribosomes don't mature properly, to the extent that they can't make proteins, and eventually the cells die.
Culver explains that a healthy ribosome has two compartments that must come together, but only when each one is mature.
Too much RbfA speeds this process up, and can result in an ineffective structure. KsgA binds with the smaller of the two compartments, holding back their union until both parts are ready. Potential Drug Target: Disrupt KsgA - RbfA Balance The findings suggest a potential drug target against the E. coli superbug could be to disrupt the balance between KsgA and RbfA.
The added benefit is that RbfA does not exist in humans. Culver says this means it may be possible to kill E. coli in infections without harming patients.
Eric Brown is a a professor of biochemistry and biomedical sciences at McMaster University in Hamilton, Ontario, and was not involved with the study. He describes Culver and Connolly's work as "creative and scholarly".
"Ribosome assembly represents a rich target for much needed antibacterial drugs to treat drug-resistant infections, and this work offers new and important insights into the process," he says.
Another study published online on 5 February in Environmental Science and Technology, shows how it may be possible to starve antibiotic resistance out of superbugs.