April 18, 2009

Researchers Getting Closer To New Type Of Antibiotic

According to a study in the Journal of Biological Chemistry, researchers have found the structure of a key genetic mechanism in bacteria, which may allow them to design a new type of antibiotic.

Information stored in genes is translated into proteins, the workhorse molecules that make up the body's structure.  DNA (deoxyribonucleic acid) chains store instructions which are copied into mRNAs (messenger ribonucleic acids). The mRNAs are then transported to ribosomes that pair with transfer RNAs which decode the gene.

Recently, research has revealed that RNA exerts control over expression, instead of being a passive middleman.

In 2002, researchers from Yale and NYU reported that the regulatory mechanisms arising from riboswitches regulate gene expression at the mRNA level by changing shape.  This change in shape governs the genetic decoding process.

Understanding how riboswitches change shape, can help researchers develop a new class of antibiotics.

The current study revealed the structure of nature's smallest known riboswitch, and detailed how its structure controls the life process in bacteria.

It's the first time scientists have been able to do so.

"The work has gained attention because interfering with riboswitches in bacteria known to cause major human infections may provide a new generation of antibiotics at a time when bacteria have become frighteningly capable of resisting current drugs," said Joseph E. Wedekind, Ph.D., the study's senior author.

"Among the bacteria now known to contain riboswitches are E. coli and streptococcus, as well as the bacteria behind forms of anthrax, gonorrhea, meningitis and dysentery. Riboswitches have not yet been found in human cells, and the hope is future riboswitch drugs will kill bacteria without side effects."

Typically riboswitches turn of the ability of an mRNA to decode its genetic message.  The current study looked at the preQ1 riboswitch, which controls the ability of bacteria to produce a molecule called queuosine.

Queuosine, also known as Q, allows gene expression despite a defect in the mRNA-ribosome-tRNA system.  Many bacteria lose their ability to produce gene products necessary to survival without Q.

Yale's Ron Breaker first revealed the mechanism by which bacteria make sure that they possess the correct amount of Q.  A riboswitch senses whether there is enough preQ1, a key precursor to Q.  If there is too much preQ1, the bacterial genes responsible for producing preQ1 are shut down.

Researchers have theorized that when preQ1 binds to the preQ1 riboswitch, mRNA shape changes to mask signals which are necessary for a productive agreement with the ribosome.  Ultimately, if too much preQ1 is present, the enzyme which makes preQ1 is shut off by the riboswitch.

Researchers were able to take snapshots of the riboswitch interacting with preQ0.  In once instance, the preQ0 binds into a buried pocket of the riboswitch.  In another instance, the riboswitch twisted into the double helix structure.

The study also revealed how the first base of the mRNA's ribosome binding site binds to a loop of the riboswitch.   

The research confirmed Breaker's findings that the preQ1 riboswitch is uncommonly small.  Its economical size allows it to function better than expected.

Wedekind's team will now search for how other bacterial species sequester their ribosome binding sites.

These findings will help researchers develop a new class of antibiotics, which would bind in place of the natural signaling molecule.  This would lock the mRNA into a stable conformation which would counter act the mRNA's ability to cause disease.

Previous studies have shown that E Coli and other disease causing bacteria are limited when genetically engineered to lack the genes for Q production.

According to Robert C. Spitale, a doctoral student who played a key role in the research, unraveling the biology of these molecules will greatly benefit our understanding of gene regulation and human disease.


On The Net:

Journal of Biological Chemistry