Cellular chaos fights infection

Researchers have identified a molecule that disrupts RNA degradation in gram-positive bacteria such as the deadly MRSA (Methicillin-resistant Staphylococcus aureus) and the microbe that causes meningitis, according to linkurl:research;https://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001287 published today in PLoS Pathogens.Treatment with this molecule leads to the accumulation of unneeded proteins that clutters the cytoplasm and ultimately results in cell death, suggesting this unexploited pathway may be used to create powerful antibiotics.

Scanning electron micrograph of methicillin-resistant Staphylococcus aureus
Image: Wikimedia commons, CDC/ Janice Carr/ Deepak Mandhalapu, M.H.S.

"I do think it's a very interesting idea and a very interesting article," said linkurl:June Scott,;https://www.microbiology.emory.edu/scott/ a microbiologist at the Emory University School of Medicine, who was not involved in the research.When developing antibiotics, researchers seek to disrupt the action of essential proteins. They have developed drugs that interrupt a cell's ability to transcribe RNA, such as rifampicin for tuberculosis treatment, or to translate RNAs into proteins, such as the broad-spectrum antibiotics tetracyclines and chloramphenicol. But to date, no drugs have targeted the RNA degradation process cells use to get rid of unneeded transcripts. "It's an underestimated form of controlling RNA levels in the cell," said molecular microbiologist linkurl:Ciaran Condon;https://www.ibpc.fr/UPR9073/equipe_Ciaran/AccueilCCondonGB.htm of the Institut de Biologie Physico-Chimique in Paris, who was not involved in this study. But in the last 5 or 6 years, he added, scientists have begun to explore targeting RNA degradation pathways as a way of "governing the level of expression of any particular gene in the cell."An RNA molecule's half life -- the time from its transcription until its degradation by ribonucleases (RNases) in the cytoplasm -- can vary widely across species. Yeast RNAs, for example, have a half-life of about 20 minutes, while a human RNA transcript can survive for several days. Staphylococcus aureus, the bacterium that causes Staph infections, and the highly-resistant MRSA strain that has plagued hospitals for the last few decades have RNA half-lives of less than five minutes.If researchers could somehow block this degradation from happening, the bacterial cell would rapidly fill up with RNA transcripts it doesn't need, said paper author linkurl:Paul Dunman;https://www.urmc.rochester.edu/mbi/resources/labs/Dunman_Lab/index.cfm of the University of Rochester School of Medicine and Dentistry. "It's kind of like chaos -- or at least that's the way I imagine it."To identify potential targets, Dunman and his team compared S. aureus's RNA turnover rate during different phases of its pathogenic lifecycle with the expression of the bacteria's RNases. They first discovered that the RNA turnover rate decreased slightly once the microbes had successfully infected their hosts, then noted a concurrent drop in the expression of rnpA, a gene that encodes a protein component of RNase P. Although RNase P is known to help form transfer RNA molecules that carry amino acids to the ribosome for protein production, the coincidental timing suggested that it may also play a role in the RNA degradation process. Sure enough, follow up in vitro experiments demonstrated RnpA's ability to break down RNA transcripts."We didn't believe it," said Dunman of the degradation capability of RnpA. "This protein has the ability to degrade RNA in a test tube, which actually freaked us out at first because it's never been described before." After screening nearly 30,000 chemical compounds, the researchers identified a molecule, RNPA1000, that interfered with RnpA's degradation ability in vitro. Testing the molecule in S. aureus-infected mice, the researchers found that treatment with RNPA1000 improved survival, suggesting that disrupting the RNA degradation process could help fight the infection.None of the mice were completely cleared of the S. aureus microbes, however, regardless of the amount of RNPA1000 used. "This indicates that there are two populations of bacteria here, one of which is susceptible to the drug and one that isn't," said Scott. It could be, she added, that the entire RNase P molecule -- and not just the RnpA protein component that RNPA1000 inhibits -- must be targeted for the treatment to be more effective.Still, this research provides the first proof of principle that RNA degradation pathways can be targeted by drugs to effectively combat bacterial infection, Dunman said. "The whole goal of our research is to not only develop therapeutics, but also to develop strategies that other people can exploit."Olson, P.D., et al. "Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis." PLoS Pathogens, doi: 10.1371/journal.ppat.1001287
**__Related stories:__***linkurl:MRSA: RIP?;https://www.the-scientist.com/news/display/53982/
11th December 2007]*linkurl:How to Find New Antibiotics;https://www.the-scientist.com/2005/10/10/20/1/
[10th October 2005]*linkurl:Barriers on the Road to New Antibiotics;https://www.the-scientist.com/2005/03/14/42/1/
[14th March 2005]*linkurl:Related F1000 evaluations;https://f1000.com/search/evaluations?query=MRSA
[10th February 2011]