When developing new antibiotics, scientists generally look to models found in nature. Because in the course of evolution, bacteria and fungi have developed many ways of killing other microorganisms. With the hospital germ Pseudomonas aeruginosa, researchers have now come across a previously unknown tactic: while most bacterial toxins attack certain vital proteins of other microorganisms or aim directly at their genetic material, the newly discovered toxin targets the RNA, which mediates the conversion of genetic information into proteins . The discovery could inspire the development of new antibiotics.
In bacteria, as in humans, animals, plants and fungi, the genetic information is stored in the DNA. However, RNA also fulfills numerous vital functions in the body: When the genetic material is converted into proteins, the so-called messenger RNA (mRNA) provides the blueprint for the respective protein as a copy of the corresponding DNA section. The transferRNA (tRNA) transports the amino acids from which the proteins are built and ensures that they are assembled in the correct order based on the template of the mRNA. So-called ribosomes ensure that mRNA and tRNA come together and can interact correctly. The ribosomes, in turn, consist largely of ribosomal RNA (rRNA). Other RNA molecules, so-called ribozymes, also catalyze various processes in the cell, including the breakdown of used RNA.
target RNA
A cell cannot survive without functional RNA molecules. This is exactly what the bacterium Pseudomonas aeruginosa uses. This bacterium is known as a hospital germ that causes pneumonia, especially in immunocompromised patients. The bacterium is naturally resistant to numerous antibiotics. A team led by Nathan Bullen from McMaster University in Hamilton, Canada, has now found that P. aeruginosa itself also secretes a toxin that acts as an antibiotic and kills other types of bacteria - in a previously unknown way: "Our research shows that that the toxin targets essential RNA molecules of other bacteria, rendering them inoperable," says Bullen's colleague John Whitney.
In numerous laboratory experiments, the research team investigated how exactly the toxin, called RhsP2, works at the molecular level. Accordingly, it is a so-called ADP-ribosyltransferase (ART), which is able to attach small appendages to other molecules and thus influence their function. The toxins of the bacteria that cause diphtheria, whooping cough and cholera work according to the same principle - but with one crucial difference: all known ART toxins target proteins, not RNA.
Approach for new antibiotics?
"RhsP2 activity is remarkably versatile," the authors write. Among other things, the toxin disrupts the activity of the tRNAs, which are supposed to bring the building blocks for the proteins to the right place. It also interferes with a ribozyme that is responsible for breaking down RNA molecules. "As a result of the inhibition of protein biosynthesis and the disruption of the breakdown of tRNAs, cell death is triggered," say the researchers. "Taken together, our data reveal a previously undescribed mechanism of bacterial antagonism and reveal a previously unknown activity of ART enzymes."
The researchers believe this discovery may help develop a new class of antibiotics that exploit the same vulnerability as the RhsP2 toxin. This could help to find treatment options against pathogens that are resistant to most existing antibiotics.
Source: Nathan Bullen (McMaster University, Hamilton, Canada) et al., Molecular Cell, doi: 10.1016/j.molcel.2022.08.015