BioEd Online

Engineered bacteria that can detect and kill human pathogens could provide a new way to treat antibiotic-resistant bacteria. Using the tools of synthetic biology, researchers have given bacteria therapeutic properties unseen in any natural strain — although they won't be injected into people any time soon.

"Our study is the first example of how synthetic biology will be useful for fighting bacterial infections," says biochemical engineer Matthew Chang, an author on the paper, which is published today in Molecular Systems Biology¹.

Chang and his team at Nanyang Technological University in Singapore have engineered a strain of Escherichia coli bacteria that attacks Pseudomonas aeruginosa, a bacterium that can cause lethal infections.

Pseudomonas aeruginosa competes with its own species by producing toxic proteins called pyocins. Chang's team exploited this molecular system by giving E. coli the genes for pyocin S5, which kills strains of P. aeruginosa that infect people. Because each pyocin targets only certain bacterial strains, the toxin will not kill other bacteria living in the body.

"Pyocins are the Pseudomonas bacterium's own species-specific antibiotics, so using pyocins instead of broad-spectrum synthetic antibiotics might help slow the spread of antibiotic resistance," says Chang.

Pyocin punch

Resistance to pyocins will probably develop more slowly than it does for other antibiotics, says microbiologist Dean Scholl of AvidBiotics in South San Francisco, California, a pharmaceutical company marketing a different type of pyocin. "So far we don't know of any genes for resistance to pyocins that move between bacterial strains on a plasmid, which is how resistance to many small-molecule antibiotics is transferred," he says.

Chang and his team hacked into another aspect of Pseudomonas biology, designing their E. coli to burst open and release pyocins only when they detect the chemical signals that Pseudomonas bacteria send to one another.

In laboratory experiments, only 1% of P. aeruginosa grown in culture with the engineered E. coli survived. Pseudomonas aeruginosa biofilms – bacterial colonies that are more virulent and resistant to antibiotics than lone cells – were also much thinner and sparser when the E. coli were present.

Chang says that the team is refining its E. coli to deliver a greater pyocin punch before moving to animal models.

"This is very elegant biology, but it seems difficult to convert it to a practical system," says David Livermore, a microbiologist at the Health Protection Agency Centre for Infections in London. At present, the treatment is effective only if the engineered E. coli cells outnumber P. aeruginosa by four to one.

"I'd also be very wary of putting live E. coli onto a burn or into the respiratory tract, which is where we often see Pseudomonas infections, but where you don't want to add bacteria," says Livermore. He thinks that the engineered bacteria might be more useful in treating infections in the gut, where bacteria are already abundant.

The study authors say that their systematic approach to engineering bacteria will make this possible too. "We designed and characterized the three biological elements – toxin production, bacteria sensing and cell lysis – separately," says bioengineer Chueh Loo Poh, another author on the study. "They're just like building blocks, so any combination of them could be interchanged to suit the biology of a different infection."

The team is already engineering another E. coli strain to target Vibrio cholerae, a bacterium that infects the human gut and causes cholera.