Biochemists have uncovered the mechanism of antibiotic resistance in bacteria
An international team of biochemists has discovered that the mechanism of bacterial resistance to antibiotics is more complex than expected. To study the work of the resistance gene, the scientists analyzed the structure of the ribosome. They also figured out how some antibiotics manage to affect resistant bacteria.
Some antibiotics attack the bacterium's ribosome when suppressing infection. This organelle synthesizes proteins, and once the antibiotic catches up with it, the process is disrupted and the bacterium dies. But some strains have developed a mechanism of defense against drugs - such bacteria are called antibiotic-resistant. The problem of resistance of pathogens to antibiotics is now extremely acute, because the longer mankind uses old drugs, the more bacteria adapt to them.
It was thought that the way to protect was simply to block the binding site using a methyl group - methylation. This function is encoded by the Cfr gene, which modifies the ribosome. As a result, the antibiotic has nothing to latch on to and the drug fails. However, researchers from the University of Illinois together with colleagues from Harvard (USA) with the help of X-ray structural analysis of the modified ribosome learned that the mechanism of bacterial defense is more complex. A paper on this was published in the journal Nature Chemical Biology.
To better understand the mechanism of blocking the actions of antibiotics, the researchers engineered a bacterial strain with the Cfr gene in the lab. They verified that this gene methylates some nucleotides in the ribosome, but does not change their position. But the scientists noticed that under the influence of Cfr, nucleotide A2062 stops rotating as it normally does.
The biochemists hypothesized that this stabilization of the nucleotide might further reduce the effectiveness of the antibiotics. To understand this, they found those bacteria in a group of resistant strains where the Cfr gene does not work, but instead contain mutant versions of another gene. This version also stops the rotation of nucleotide A2062, but no methylation occurs. It turned out that changing the position of this nucleotide in space also prevents the drug from attaching to the ribosome.
In addition, the researchers checked how some antibiotics can act on resistant bacteria. For the experiments, they chose the recently synthesized iboxamicin and examined its structure during binding to the modified ribosome. The biochemists saw that the shape of iboxamycin allows it to penetrate the gap of the binding site.
"It just binds to the ribosomes and acts like it doesn't care if it was methylated or not. It easily overcomes several of the most common types of drug resistance," said paper co-author Yuri Polikanov.
According to the researchers, understanding the two-component defense mechanism of resistant bacteria, as well as the structure of the modified ribosome may help in the creation of a new generation of antibiotics active against strains with multiple resistance.