Bacteria use a variety of methods to fight off the medications designed to destroy them. Ribosome-modifying enzymes are one of these weapons that are most common. These enzymes are becoming more widespread, turning up in clinical samples from bacteria with various drug resistances all over the world.
Now, researchers have seen one significant family of these enzymes in operation for the first time. Images demonstrate how the enzymes attach to a specific location on the bacterial ribosome and squeeze it like a pair of tweezers in order to remove and modify an RNA nucleotide. The research, conducted by academics at Emory University, was published in the PNAS journal Proceedings of the National Academy of Sciences.
The advanced technique of cryoelectron microscopy made the ultra-high-resolution, three-dimensional snapshots possible.
“Seeing is believing,” said Christine Dunham, Emory professor of chemistry and co-corresponding author of the paper. “The minute you see biological structures interacting in real life at the atomic level it’s like solving a jigsaw puzzle. You see how everything fits together and you get a clearer idea of how things work.”
The insights may lead to the design of new antibiotic therapies to inhibit the drug-resistance activities of RNA methyltransferase enzymes. These enzymes transfer a small hydrocarbon known as a methyl group from one molecule to another, a process known as methylation.
“Methylation is one of the smallest chemical modifications in biology,” says Graeme Conn, professor of biochemistry in Emory’s School of Medicine and co-corresponding author of the paper. “But this tiny modification can fundamentally change biology. In this case, it confers resistance that allows bacteria to evade an entire class of antibiotics.”
Both Conn and Dunham are also members of the Emory Antibiotic Resistance Center.
First author of the paper is Pooja Srinivas, who did the work as a PhD candidate in Emory’s graduate program in molecular and systems pharmacology. She has since graduated and is now a postdoctoral fellow at the University of Washington.
Dunham is a leading expert on the ribosome — an elaborate structure that operates like a factory within a cell to manufacture proteins. Proteins are the machines that make cells run while nucleic acids such as DNA and RNA store the blueprints for life. The ribosome is made mostly of RNA, which does not just store information but can also act as an enzyme, catalyzing chemical reactions.
One goal of Dunham’s lab is to find ways to manipulate bacterial ribosomes to make them more susceptible to antimicrobials. If an antimicrobial successfully inactivates bacterial ribosomes, that shuts down the manufacturing of proteins essential for bacterial growth and survival.
The idea is to exploit differences in human cellular ribosomes and bacterial ribosomes, so that only the bacteria is targeted by an antimicrobial drug.
Antimicrobials, however, need to get past bacterial defenses.
“It’s like a molecular arms race,” Dunham explains. Bacteria keep evolving new weapons as a defense against drugs, while scientists evolve new strategies to disarm bacteria.
Conn is a leading expert in the bacterial defense weapons known as ribosomal RNA methyltransferase enzymes. This family of enzymes was originally discovered in soil bacteria. They are now increasingly found in bacterial infections in people and animals, making these infections harder to treat.
“They keep turning up more and more often in clinical samples of some nasty bacterial pathogens in different parts of the world,” Conn says.
