Bacteria modify their ribosomes when exposed to widely used antibiotics, according to research published today in Nature Communications. Subtle changes could be sufficient to alter the binding site of drug targets and constitute a potential new mechanism of antibiotic resistance.
Escherichia coli It is a common bacteria that is often harmless but can cause serious infections. The researchers exposed E. coli to streptomycin and kasugamycin, two drugs that treat bacterial infections. Streptomycin has been a staple in the treatment of 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 disrupt the bacteria’s ability to make new proteins by specifically attacking their ribosomes. These molecular structures create proteins and are in turn 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 adjust protein production.
The study found that, in response to antibiotics, E. coli begins to assemble new ribosomes that are slightly different from those produced under normal conditions. Depending on the antibiotic used, the new ribosomes lacked certain tags. The tags were specifically lost in regions where antibiotics bind and stop protein production. The study found that this made the bacteria more resistant to drugs.
“We believe that the bacteria’s ribosomes could be altering their structure enough to prevent an antibiotic from binding effectively,” says Anna Delgado-Tejedor, first author of the study and doctoral student at the Center for Genomic Regulation (CRG) of Barcelona.
Bacteria are known to develop resistance to antibiotics in different ways, including mutations in their DNA. Another common mechanism is its 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 a completely new survival strategy. “E. coli is altering its molecular structures with remarkable precision and in real time. It is a stealthy and subtle way of avoiding drugs,” says Dr. Eva Novoa, corresponding author of the study and CRG researcher.
The researchers made these findings using advanced nanopore sequencing technology, which reads RNA molecules directly. Previous techniques processed RNA molecules in such a way as to eliminate 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 chemical modifications are lost in the first place. Additional research could explore the underlying biology of the adaptive mechanism and discover 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 projected to claim 39 million more lives by 2050.
“If we can dig deeper and understand why they are removing these modifications, we can create new strategies that prevent bacteria from removing them in the first place or create new drugs that bind more effectively to the altered ribosomes,” says Dr. Novoa.