Modified ribosomes could be a possible mechanism of antibiotic resistance

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Bacteria modify their ribosomes when exposed to widely used antibiotics, according to research published in Nature Communications. The subtle changes might be enough to alter the binding site of drug targets and constitute a possible new mechanism of antibiotic resistance.

Escherichia coli is a common bacterium which is often harmless but can cause serious infections. The researchers exposed E. coli to streptomycin and kasugamycin, two drugs which treat bacterial infections. Streptomycin has been a staple in treating tuberculosis and other infections since the 1940s, while kasugamycin is less known but crucial in agricultural settings to prevent bacterial diseases in crops.

Both antibiotics tamper with bacteria's ability to make new proteins by specifically targeting their ribosomes. These molecular structures create proteins and are themselves made of proteins and ribosomal RNA. Ribosomal RNA is often modified with chemical tags that can alter the shape and function of the ribosome. Cells use these tags to fine tune protein production.

The study found that, in response to the antibiotics, E. coli begins to assemble new ribosomes that are slightly different from the ones produced under normal conditions. Depending on which antibiotic is used, the new ribosomes lacked certain tags. The tags were specifically lost in the regions where antibiotics latch on to and halt protein production. The study found this made the bacteria more resistant to the drugs.

"We think the bacteria's ribosomes might be altering its structure just enough to prevent an antibiotic from binding effectively," says Anna Delgado-Tejedor, first author of the study and Ph.D. student at the Center for Genomic Regulation (CRG) in Barcelona.

Bacteria are known to develop antibiotic resistance in different ways, including mutations in their DNA. Another common mechanism is their ability to actively pump and transport antibiotics out of the cell, reducing the concentration of the drug inside the cell to levels that are no longer harmful.

The study is evidence of an entirely new survival strategy. "E. coli is altering its molecular structures with remarkable precision and in real time. It's a stealthy and subtle way of dodging drugs," says Dr. Eva Novoa, corresponding author of the study and researcher at the CRG.

The researchers made the findings using advanced nanopore sequencing technology, which read RNA molecules directly. Previous techniques would process RNA molecules in such a way that it would remove the chemical modifications.

"Our approach has allowed us to see the modifications as they are, in their natural context," says Dr. Novoa.

The study does not explore why or how the chemical modifications are lost in the first place. Further research could explore the underlying biology of the adaptive mechanism and uncover new ways to combat one of the biggest looming crises in global health. Global antimicrobial resistance has claimed at least one million lives each year since 1990 and is forecast to claim 39 million more lives between now and 2050.

"If we can delve deeper and understand why they are shedding these modifications, we can create new strategies that prevent bacteria from shedding them in the first place or make new drugs that more effectively bind to the altered ribosomes," says Dr. Novoa.

More information: Native RNA nanopore sequencing reveals antibiotic-induced loss of rRNA modifications in the A- and P-sites, Nature Communications (2024). DOI: 10.1038/s41467-024-54368-x

Journal information: Nature Communications

Provided by Center for Genomic Regulation