Pseudomonas aeruginosa is a common bacterium that can be found in many places, from soil and water to the surface of your skin or medical equipment. It is also a common nosocomial pathogen that can for example infect the lungs, burns or wounds and lead to pneumonia, sepsis or other infections with life-threatening consequences, especially in immunodepressed individuals. Unfortunately, P. aeruginosa is resistant to many antibiotics (and pretty good at developing resistance to new treatments), can survive and even thrive on many surfaces, and can organize in biofilms that are particularly difficult to destroy.
Synthetic biologists at Nanyang Technological University in Singapore have now created an Escherichia coli bacterium that specifically seeks out and kills P. aeruginosa.
Such bioengineered bacteria are not new: the same research group had reported earlier the development of an E. coli that could make an antimicrobial peptide and release it in presence of its target P. aeruginosa; other researchers at the University of Maryland have made a bacterium that seeks out cancer cells and delivers toxic chemicals. What’s really interesting in the new E. coli presented by Matthew Chang and colleagues is that it combines several tactics already employed individually in other bioengineered bacteria.
The researchers inserted genes in E. coli to make it capable of (1) detecting the presence of P. aeruginosa, (2) moving towards the pathogenic bacteria, and (3) producing compounds to efficiently kill these harmful bacteria (see schematic picture here). More specifically, the bioengineered E. coli makes a protein that senses a molecule used by P. aeruginosa to assess its own population density (a process called quorum sensing) – that’s phase (1), detection. The E. coli detection protein then binds to the P. aeruginosa quorum sensing molecule to form a complex that will activate phases (2) and (3): the bioengineered E. coli will now move towards the P. aeruginosa colony, following the gradient of quorum sensing molecules the colony produces, and will start producing two molecules to attack and kill the P. aeruginosa bacteria. An enzyme called DnaseI will cut through the protective biofilm matrix in which the P. aeruginosa bacteria are embedded, exposing them to the other compound produced by the bioengineered E. coli, the antimicrobial peptide microcin S.
The beauty of the system resides in the combination of several properties:
– the bioengineered E. coli only activates its killing properties if it detects the presence of its target P. aeruginosa,
– the production of the antimicrobial molecules is integrated with the migration of the E. coli bacterium towards P. aeruginosa, directing the attack specifically towards the target (whereas a traditional antibiotic treatment will wipe off all bacteria indiscriminately, the pathogenic ones as well as the beneficial microbiota in the gut),
– the production of the antimicrobial peptide is accompanied by the production of a molecule that will help the antimicrobial peptide reach its target by degrading the biofilm matrix that surrounds it.
Preliminary tests in mice infected with P. aeruginosa seem promising: the mice that received the bioengineered E. coli had fewer pathogenic bacteria than mice given ordinary E. coli a few hours after the treatment, and no harmful side effect was observed. It will probably be quite a while before such a strategy can be used to treat humans though. Besides improving the technique (e.g. improving the bacterium’s targeting system, its ability to degrade biofilms), the safety and effectiveness of bioengineered bacteria will have to be demonstrated in humans. And that’s not to mention the regulatory hurdles that come along with the potential use of genetically modified organisms. Regardless of how soon therapeutic applications may come to reality, the idea of designing tiny killer microorganisms to help us get rid of other nasty tiny invaders is interesting.
Hwang IY, Tan MH, Koh E, Ho CL, Poh CL, & Chang MW (2013). Reprogramming Microbes to Be Pathogen-Seeking Killers. ACS synthetic biology PMID: 24020906