MADISON, Wis., U.S.: The threat antibiotic-resistant pathogens pose to the global community is continuing to rise. With research showing that German patients with severe periodontitis are already at risk and recent statistics revealing that at least 2 million people per year in the U.S. contract an antibiotic-resistant infection, a vast amount of effort is needed to address the issue. In a positive step in this regard, researchers have recently repurposed the gene-editing tool CRISPR to study which genes are targeted by particular antibiotics, providing clues on how to improve existing antibiotics or develop new ones.
“Most people, when they think about CRISPR, think about gene editing,” said Dr. Jason Peters, an assistant professor of pharmaceutical sciences at the University of Wisconsin–Madison. Working with colleagues from the university and from the University of California, San Francisco, Peters developed a new technique, known as Mobile-CRISPRi, which allows the screening of antibiotic function in a wide range of pathogenic bacteria.
CRISPRi is a defanged form of CRISPR and has been engineered to be unable to cut DNA. Instead, it sits on the DNA, blocking other proteins from gaining access to and turning on a particular gene. The result is a lower expression of the gene and a reduced amount of the protein it codes. Because of this, the researchers showed that if they decreased the amount of protein targeted by an antibiotic, bacteria became much more sensitive to lower levels of the drug, something Peters and his team believe is evidence of a gene-drug association.
To make the system mobile, Peters turned to conjugation, a discovery made by the late University of Wisconsin–Madison Professor of Genetics Joshua Lederberg, which earned him a Nobel Prize in 1958. Using conjugation, the researchers transferred Mobile-CRISPRi to the pathogens Pseudomonas, Salmonella, Staphylococcus and Listeria, among others. “What that means is that you can now do studies on how antibiotics work directly in these pathogens. That could give us a better clue about how these drugs work in the different organisms and potentially what we can do to make them better,” explained Peters.
Using a form of bacterial sex, the researchers then transferred Mobile-CRISPRi from common laboratory strains into diverse bacteria, even including a little-studied microbe that makes its home on cheese rinds. This ease of transfer makes the technique a boon for scientists studying any number of bacteria that cause disease or promote health. According to the researchers, because the system reduces the production of protein from targeted genes, it allows them to identify how antibiotics inhibit the growth of pathogens. That knowledge can help direct research to overcome resistance to existing drugs, they believe.
Additionally, in 2010, Vibrio casei was found on the rind of a French cheese by one of Peters’ collaborators, Dr. Rachel Dutton from the University of California, San Diego. According to the scientists, the new method was quickly transferred to the strain, opening up new avenues for understanding how the bacteria colonizes and helps age cheese. Owing to this, Peters believes that this is another proof of concept, demonstrating that Mobile-CRISPRi should be useful for any number of previously understudied bacteria.
The study, titled “Enabling genetic analysis of diverse bacteria with Mobile-CRISPRi,” was published in Nature Microbiology on Jan. 7, 2019.
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