Antimicrobial resistance — when bacteria and fungi defend themselves against the drugs design to kill them — is an urgent threat to global public health , according to the Centers for Disease Control and Prevention.
To combat this threat, the Gerdt Lab at Indiana University Bloomington studies how to weaken bacteria's defenses against viruses.
"Bacteria get sick, too," said J.P. Gerdt, assistant professor of chemistry in the College of Arts and Sciences at IU Bloomington. "Our lab tries to understand how their immune systems work so we can figure out how to inhibit them."
Bacteriophages, the viruses that attack and kill bacteria, can be a useful alternative to antibiotics. Antibiotics kill not just pathogens but also good bacteria, but bacteriophages can be deployed in a more targeted way to kill just one problematic strain of bacteria, leaving beneficial microbes untouched.
Bacteriophages are also useful in agriculture because they provide a more targeted approach to killing bacteria. Whereas many antibiotics tend to kill not just infection- and disease-causing bacteria but good bacteria as well, bacteriophages can be deployed to kill just one strain of bacteria.
However, just as bacteria have evolved antibiotic resistance, they can also become immune to bacteriophages.
That is where the Gerdt Lab's work comes in. Former lab member Zhiyu Zang, now a post-doctoral candidate at the Swiss Federal Technology Institute of Lausanne, discovered a chemical molecule that when paired with the bacteriophage helps the virus overwhelm a bacteria's immune system.
This finding was revealed in Zang and Gerdt's paper "Chemical inhibition of a bacterial immune system," recently published in Cell Host and Microbe.
While antibiotics will likely remain the first line of defense for human bacterial infections, the Gerdt Lab's discovery could still apply to hard-to-treat infections in humans. It could also be applied in places like agriculture, where antibiotic overuse can worsen the spread of antibiotic resistance.
A needle in a haystack
Just as millions of bacteria strains exist, there are potentially as many chemical molecules that could be deployed to inhibit bacterial immune systems. Gerdt hopes that in 10 to 15 years, his lab will create a library of inhibitors for different bacteria.
Gerdt and Zang's strategy with this paper was to begin research with a bacterium that was relatively easy and safe for undergraduates to study. Students like Olivia Duncan, who was an undergraduate when she worked in Gerdt's lab, helped Zang and Gerdt find molecules that chemically inhibited that bacterium's immune system.
"Our study is important not just because we found the first example of a small molecule that can inhibit a bacteria's immune system," Zang said. "It's also important because the immune system we're studying in this paper is present in around 2,000 different bacteria species."
This finding allows them to develop general rules and tools for a targeted approach to pathogenic bacteria with similar immune systems like Pseudomonas aeruginosa or Staphylococcus aureus, both often resistant to antibiotics and the cause of many deadly hospital-acquired infections.
Duncan, who is the second author on the paper and currently a Ph.D. student at Cornell University, worked with Zang to identify a chemical molecule that helped a virus evade the bacterium's immune system.
"Our goal is to have a collection of inhibitors that will work for different immune systems," Gerdt said. "We hope that this paper will be a catalyst for other labs to work on this with us as a community. That's what makes this paper so exciting: We're starting something new and seeing where it takes off."
