Unique Mechanism Identified in Bacteria as Potential Target for Developing New Antibiotics

Researchers from Florida Atlantic Universitys Charles E. Schmidt College of Medicine have identified a unique mechanism in bacteria that has the potential to serve as a target for developing new antibiotics for diseases such as AIDS and soft tissue infections including respiratory and urogenital tracts, which are currently difficult to treat. The results of these findings were published in an article titled Novel One-step Mechanism for tRNA 3-End Maturation by the Exoribonuclease RNase of Mycoplasma gentialium in the current issue of the Journal of Biological Chemistry.

Co-authors of the article are Ravi K. Alluri, a pre-doctoral student in the department of biomedical science and Zhongwei Li, PhD, associate professor of biomedical science in FAUs Charles E. Schmidt College of Medicine.

Li and Alluri explain that every organism lives on the same principle that genes direct the production of proteins. This process depends on a set of small RNAs called tRNAs that carry the building blocks of proteins. A tRNA is produced from its gene initially as a precursor that contains extra parts at each end (5 and 3 ends) and sometimes in the middle. These extra parts must be removed through RNA processing before tRNA can work during protein production. The processing of tRNA 5 end has been known for quite some time and work on this enzyme has received a Nobel Prize. Processing of the 3 end is much more complicated and has only been revealed in some organisms more recently. Organisms that have nucleus in their cells, including humans, appear to process the 3 end of tRNA in a similar way. A tRNA must be precisely processed before it can carry a building block for proteins.

Intriguingly, bacteria appear to process the 3 end of tRNA very differently, said Alluri. And we are still trying to reveal the various enzymes called RNases, which remove the 3 extra parts of tRNA precursors.

Some of the RNases cut the RNA in the middle, while others trim the RNA from the 3 end. Most of the bacterial pathways involve multiple RNases to complete tRNA 3 processing.

Knowing how tRNA is processed in different types of bacteria is important not only for understanding how bacteria live, but also for developing novel antibiotics that specifically control bacterial pathogens, says Li.

One such pathogen is the bacterium Mycoplasma genitalium, which is the second smallest known free-living organism that is thought to cause infertility. Alluri and Lis current work focuses on this bacteriumits genome only contains about 10 percent of the genes found in other common bacteria. Surprisingly, this bacterium contains none of the known RNases for tRNA 3 processing and hence it has to use a different RNase to do so.

What we have discovered with Mycoplasma genitalium is that it uses a completely different RNase called RNase R to process the 3 end of tRNA, says Alluri. RNase R can trim the 3 extra part of a tRNA precursor to make a functional tRNA. It is even smart enough to recognize some structural features in the tRNA and tell where the trimming has to stop without harming the mature tRNA.

The ability of RNase R to completely remove the 3 extra RNA bases in a single-step trimming reaction represents a novel mechanism of tRNA 3 processing. Other mycoplasmas generally have small genomes and likely process tRNA in the same way. Using only one enzyme for this complicated task saves genetic resources for mycoplasmas.

Importantly, blocking the function of RNase R in mycoplasmas can stop protein production and kill the bacteria, making RNase R an excellent target of new antibiotics for treatment of mycoplasma infection, says Li.