New Discovery May Explain Why Certain Infections Refuse to Go Away

There is a major concern in the medical community that bacteria are becoming increasingly resistant to antibiotics. Now, new research out of the University of Utah has revealed a mechanism that could help make clear why infections will not just go away.

Multi-Drug Resistant Bacteria. Image Courtesy of Dr Graham Beards

Researchers say bacteria make use of the newly-discovered mechanism to adapt rapidly to environmental stress. This improves their chances of survival in hosts.

With this mechanism, pathogenic bacteria adjust the precision with which they make proteins, which are needed for most work in cells. The microbes basically change certain molecular biology rules to give themselves a better chance for survival.

This discovery, published in Nucleic Acids Research, may help explain why some common infections, including urinary tract infection and sepsis, persist. It could also provide guidance as regards targets for new anti-microbial treatments and vaccines, according to pathology professor Matthew Mulvey.

Adapting for survival

Bacteria should ideally be in danger when exposed to certain environments or factors, including antibiotics and acidic surroundings. These could render useless one or several vital pathways, putting the microbes in jeopardy. However, they often withstand such stressors and go on living.

How do these microorganisms survive? Researchers have found that they can alter some basic principles of molecular biology to make this possible.

Scientists believe that genes carry instructions for making a specific protein. A molecule known as transfer RNA (tRNA) makes use of these instructions to regulate protein production.

When bacteria are exposed to stressors, the tRNA-mediated process undergoes random changes quickly to alter the array of proteins in a cell. This can lead to the production of new proteins that could help a microbe to live on.

Why infections persist

Study co-author Matthew Blango, Ph.D., a former graduate student in the lab of Mulvey, initiated this discovery by chance. He chanced upon what is called MiaA, which is an enzyme in bacteria. This was found to be extra responsive to environmental stress and to play a part in protein expression.

Blango created a variant of very pathogenic bacteria lacking the gene for encoding MiaA. And microbes without MiaA were found to grow poorly and not be able to cause urinary tract infection or sepsis in mice.

“Every kind of stress we exposed the MiaA-deficient strain to seemed to cause problems,” said Blango, a junior research group leader at the Leibniz Institute for Natural Product Research and Infection Biology. “So, we really thought that this protein might be playing an important role in gene regulation.”

Bacteria also did not grow properly and could not cause infections when researchers made the microbes express excess MiaA. According to Blango, there seems to be “a Goldilocks zone, where just the right amount of MiaA allows the optimal stress response.”

Brittany Fleming, a co-first author, went further to probe the effects of MiaA imbalance. She found that getting rid of the enzyme resulted in random “frameshifting.” This is an error in which transfer RNA conveys three-letter genetic codes for translation into proteins that are out of line by a letter. As an example, “cat cat gta” could become “atc atg ta…,” according to the researchers.

This frameshifting may result in poor protein production or the production of defective proteins in bacteria.

Researchers also found that modifying MiaA levels could impact the availability of crucial metabolites for key stress response pathways in microbes. As such, this can tell on their ability to withstand stress.

The next target for the researchers will be to find out how environmental stress changes MiaA levels in bacteria, revealed Mulvey.