Researchers at St. Louis University say they have discovered new information about how antibiotics like azithromycin stop staph infections, and why staph sometimes becomes resistant to drugs. The team, led by Mee-Ngan F. Yap, Ph.D., assistant professor of biochemistry and molecular biology, believe their evidence suggests a universal, evolutionary mechanism by which the bacteria elude this kind of drug, offering scientists a way to improve the effectiveness of antibiotics to which bacteria have become resistant.  Their study (“Sequence selectivity of macrolide-induced translational attenuation”) was published in PNAS.

Staphylococcus aureus  is a strain of bacteria that frequently has become resistant to antibiotics, a development that has been challenging for doctors and dangerous for patients with severe infections. Dr. Yap and her research team studied staph that had been treated with the antibiotic azithromycin and learned two things: One, it turns out that the antibiotic isn't as effective as was previously thought. And two, the process that the bacteria use to evade the antibiotic appears to be an evolutionary mechanism that the bacteria developed in order to delay genetic replication when beneficial.

The team studied the way antibiotics work within the ribosome. When the bacteria encounter a potential problem in copying its genetic material, as posed by an antibiotic, it has a mechanism to thwart antibiotic inhibition by means of “ribosome stalling” that is mediated by special upstream peptide elements.

As the bacteria's ribosome copies the strings of genetic code, ribosome stalling at upstream elements often promotes the rearrangement of messenger RNA and activates downstream translation of the resistance gene. Many resistant pathogens exploit this mechanism to upregulate antibiotic resistance genes, and so survive even in the presence of antibiotics. In effect, the delay allows the bacteria to prepare a defense against the antibiotic further down the line of genetic code.

Dr. Yap found that the azithromycin-bound ribosomes do not simply stall at random residues, but only at specific sites. Intriguingly these residues seem to be the preferred stalling site in the ribosome stalling peptide elements that stop genetic activity.

“Although it has long been assumed that macrolides inhibit translation after the synthesis of a few residues, we found that stalling could occur at any point during translation. Our results reveal a striking conservation of stalling motifs among all known arrest peptides that strongly suggests a universal ribosome stalling mechanism,” wrote the investigators.

“Here we describe, to our knowledge, the first genome-wide snapshot of ribosome distribution along messenger RNAs in Staphylococcus aureus,” noted Dr. Yap. “By globally mapping the position of stalled ribosomes in azithromycin-treated staph, we identified the proteins affected by this antibiotic. Our results reveal a striking similarity of stalling motifs that strongly suggests a universal stalling mechanism,” according to Dr. Yap.

She added that the team has identified what appears to be an evolutionary mechanism developed by bacteria to counteract the type of antibiotics that includes azithromycin, called macrolides.”

Dr. Yap hopes this new understanding of how antibiotic resistance occurs will offer opportunities to improve existing drugs' effectiveness and give doctors more tools to help patients with severe infections.








This site uses Akismet to reduce spam. Learn how your comment data is processed.