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“I love thinking outside the box when it comes to the antibiotic resistance problem,” said J.P. Gerdt, assistant professor of chemistry at Indiana University Bloomington.
Photo Credit: Chris Meyer, Indiana University
Scientific Frontline: "At a Glance" Summary
- Main Discovery: Identification of a small chemical molecule that actively inhibits bacterial immune defenses, enabling bacteriophages to successfully infect and destroy bacteria that would otherwise resist viral attack.
- Methodology: Researchers screened a commercial compound library against a model bacterium to isolate specific molecules capable of suppressing the bacteria's immune response to bacteriophages.
- Key Data: The specific bacterial immune system mechanism targeted by the discovered molecule is present in approximately 2,000 distinct bacterial species.
- Significance: Offers a potential solution to antimicrobial resistance by potentiating phage therapy, allowing for the precise elimination of pathogens like Staphylococcus aureus without harming beneficial microbiomes, unlike broad-spectrum antibiotics.
- Future Application: Development of a comprehensive library of bacterial immune inhibitors over the next 10 to 15 years for use in agriculture and treating hard-to-cure human infections.
- Branch of Science: Biochemistry and Microbiology
- Additional Detail: These findings were published in the journal Cell Host and Microbe in a paper titled "Chemical inhibition of a bacterial immune system."
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| After leaving the Gerdt Lab for a postdoctoral position at the Swiss Federal Technology Institute of Lausanne, Zhiyu Zang focused on the human immune system. Photo Credit: Courtesty of Zhiyu Zang |
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.
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Undergraduates like Joy Seo, above, play an important role in J.P. Gerdt's lab by advancing the understanding of bacteria's defenses against viruses.
Photo Credit: Chris Meyer, Indiana University
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 and Zang worked their way through a commercial compound library of chemical molecules until they found the one 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.”
A culture of curiosity
“J.P. is open to where the science takes him,” said Duncan, who is the second author on the paper and currently a Ph.D. student at Cornell University.
Duncan said that she loved working in the Gerdt lab because he instilled in her and her fellow researchers a sense of inquisitiveness. In each lab meeting, Gerdt requires every participant to come armed with at least one question for that day’s presenter.
It’s this sense of curiosity that motivates Gerdt to push for solutions to the problem of antibiotic resistance.
“I get excited trying to think about the non-obvious way to solve these problems,” Gerdt said. “Is our solution simple enough to be adopted widespread? I’m not sure yet, but it’s the process of thinking outside the box and seeing those alternative strategies work that’s thrilling.”
Published in journal: Cell Host and Microbe
Title: Chemical inhibition of a bacterial immune system
Authors: Zhiyu Zang, Olivia K. Duncan, Dziugas Sabonis, Iana Fedorova, Yun Shi, Gause Miraj, Shuai Le, Jun Deng, Yuhao Zhu, Yanyao Cai, Chengqian Zhang, Garima Arya, Shelley A.H. Dixon, Steven P. Angus, Breck A. Duerkop, Haihua Liang, Robert H. Pepin, Thomas Ve, Joseph Bondy-Denomy, Giedre Tamulaitiene, and Joseph P. Gerdt
Source/Credit: Indiana University Bloomington | Christiane Wisehart
Reference Number: bchm020426_01