An Indiana University biologist is investigating a way to tackle the deadly issue of antibiotic drug resistance.
The federal Centers for Disease Control and Prevention lists fighting the threat of antibiotic resistance as a public health priority. According to the CDC, at least 2.8 million people in the U.S. will get an antibiotic-resistant infection each year. More than 35,000 of those infected will die.
Julia van Kessel, assistant professor in the IU Bloomington College of Arts and Sciences Department of Biology, is studying aspects of “quorum sensing,” a form of cellular communication that helps microorganisms detect whether their population numbers are large enough to perform an action, such as mounting an attack on the human body. By collecting fundamental data critical to understanding quorum sensing and how it impacts bacterial pathogenesis, van Kessel and her lab are working to discover new methods to fight infections.
One study in the van Kessel lab involves bacterial proteins. Bacteria use proteins to compress and wind their DNA into their small cellular spaces. These proteins also have an important role in controlling what genes are expressed based on how much the proteins compact that region of the chromosome.
In the recent study published in the journal Nucleic Acids Research, researchers in the van Kessel lab showed that one of these compacting proteins called H-NS competes with another protein called LuxR in the cell to control expression of genes for bioluminescent light production. H-NS is normally tightly bound to DNA at the bioluminescence region, but LuxR can outcompete H-NS and turn on the light genes when cells are at high numbers and acting as a group. This is important because LuxR controls hundreds of genes in the bacterial genome in response to changes in population number.
“While H-NS is only one of the proteins with which LuxR can compete, there are likely many others that we have yet to uncover,” says van Kessel. “LuxR-type proteins control toxin secretion, biofilm formation, and motility, among other activities in bacteria. Thus, our understanding of how LuxR competes with other proteins will help us learn how genes are expressed.”
Learning how genes are expressed could ultimately provide a new weapon against bacteria-caused diseases such as tuberculosis and cholera.
Another study in the van Kessel lab explores how bacteria harvest DNA from the environment and integrate it into their own cells.
“Taking up DNA from their environment and bringing it into their cells,” notes van Kessel, “is one way that genes can be transferred between bacteria to generate antibiotic resistance.”
Researchers in the van Kessel lab investigated the proteins that control DNA uptake in five species of Vibrio bacteria. Vibrios are pathogenic bacteria that cause cholera, gastroenteritis, sepsis, and necrotizing skin diseases.
Their results, published in the American Society for Microbiology open access journal mBio, show that DNA uptake is controlled by different proteins depending on the species—and sometimes even the strain—of Vibrio. In addition, species exhibited a range of DNA uptake levels from very high to non-existent. It is possible that vibrios adapted to specific niches, such as those of a host organism for pathogenic strains, might lose the ability to take up DNA if it were no longer beneficial. Conversely, DNA uptake might be more advantageous for strains existing free-living in the ocean that are more likely to be in close proximity to other strains and benefit from the uptake of new DNA sequences.
With increased knowledge about how quorum sensing and proteins control pathogenesis in bacteria, van Kessel hopes to develop drugs that target the quorum sensing pathway. When bacteria cannot use quorum sensing to count their numbers, they do not know when to launch their “attack” and cannot cause disease.
Most antibiotics that are currently used to treat disease work by preventing bacterial cell growth. They are quite effective, but they also have a high potential to generate antibiotic resistance. Conversely, if drugs that block quorum sensing are used, they would stop expression of virulence genes but not kill the bacteria. This would minimize the rate of antibiotic resistance, and the immune system could clear the infection.
“It’s like taking the weapons away from the army but not killing the soldiers,” says van Kessel. “It’s an effective strategy to stop the war with much less damage.”
Research in the van Kessel lab is funded in part by a MIRA from the National Institutes of Health.