Researchers Engineer Bacteria to Hunt Down Pathogens in the Gut

A global team of synthetic biologists and bioengineers is taking their fight against antibiotic-resistant bacteria to a new front – the gut.

University of Maryland (UMD) Department of Chemical and Biomolecular Engineering (ChBE) alumnus Matthew Wook Chang (Ph.D. ’03) and a team of researchers from the National University of Singapore, Cornell University, and UMD’s Fischell Department of Bioengineering are on a mission to train bacteria to prey on pathogens in the gastrointestinal (GI) tract. Their latest findings were recently published in Nature Communications.

“Our work represents a potential novel antimicrobial strategy where probiotics are reprogrammed to prevent and treat target diseases,” said Chang, associate professor with the National University of Singapore’s Department of Biochemistry within the Yong Loo Lin School of Medicine. “Using an infection as a testbed, we demonstrated the prophylactic and therapeutic efficacy of reprogrammed probiotics against a human pathogen in animals.”

"Dr. Chang has rapidly become one of the world’s leaders in synthetic biology, having established an entire national center in Singapore,” said William E. Bentley, director of the University of Maryland Robert E. Fischell Institute for Biomedical Devices, co-author of the Nature Communications paper, and former postdoctoral advisor to Chang.

Chang’s work targets the pathogen, Pseudomonas aeruginosa (P. aeruginosa), a microbe he began working with while at the University of Maryland, in collaboration with Bentley and U.S. Environmental Protection Agency biochemist Freshteh Toghrol. P. aeruginosa is an antibiotic-resistant bacterium linked to hospital-acquired infections and certain inflammatory bowel diseases.

In earlier work, Chang developed a probiotic strain of E. coli to respond to P. aeruginosa by seeking it and manufacturing a targeted antibiotic protein. In this most recent effort, Chang collaborated with UMD and Cornell University researchers to engineer E. coli to destroy P. aeruginosa by honing the targeting functions as well as the means to get the drug – pyocin – to the P. aeruginosa bacterium. The group demonstrated this concept in both nematode worm and mice models.

Precision – and efficiency – are key, particularly when it comes to hunting down pathogens in the GI tract. Here, antibiotic therapies often kill good bacteria while on the hunt for pathogens, and this process can lead bacteria to grow resistant to antibiotics altogether.

While the engineered E. coli strain demonstrated an ability to sense the P. aeruginosa pathogen and accelerate bacterial clearance from the gut in both model systems, Chang and his team employed an anti-biofilm enzyme, dispersin B (DspB), to aid in wiping out the pathogen completely.

Not only did Chang and his researchers eliminate the infecting bacteria from mice, they were also able to use the engineered E. coli strain as a prophylactic to prevent P. aeruginosa colonization.

“The novelty of this work not only lies in the specific antimicrobial activity against the target pathogen, but also provides a highly modular platform that can easily be customized for other therapeutic activities,” Chang said. “For instance, the therapeutic specificity of the reprogrammed probiotics can be readily modulated by plugging in the antimicrobials that are effective against other target infectious pathogens. Furthermore, as we showed that the reprogrammed probiotics can serve as effective delivery vehicles to the gastrointestinal tract, other biological molecules can be produced and delivered to modulate the gut microbiota and the host cell activity.

In addition to Chang and Bentley, In Young Hwang, Elvin Koh, Adison Wong, and Yung Seng Lee of the National University of Singapore contributed to this work, along with John C. March of Cornell University’s Department of Biological and Environmental Engineering.

Hwang, Koh, and Wong are affiliated with the Department of Biochemistry, Yong Loo Lin School of Medicine, at the National University of Singapore (NUS), as well as the NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), Life Sciences Institute. Lee is affiliated with SynCTI and the Department of Paediatrics at the NUS Yong Loo Lin School of Medicine.

This research was funded in part by the U.S. Department of Defense, Defense Threat Reduction Agency.

Published May 26, 2017