Synthetic bio and dual-use anti-microbials

By Daniel McGown

Two articles were published in ACS Synthetic Biology this week, one from an MIT team and another from a team at Nanyang Technological University, iteratively outlining an approach for the custom design of a microbial hunter-killer against a pathogenic species.

In the first paper, Saurabh Gupta, Eran Bram, and Ron Weiss outlined proof of concept construction of an E. coli strain modified to do two novel things: 1) detect a quorum sensing signal emitted by Pseudomonas aeruginosa and 2) upon detection secrete a chimeric exotoxin designed to specifically destroy P. aeruginosa cells and nothing else. This use of passive detection to trigger an active and specific offense effectively converts the E. coli strain into a trap waiting for just P. aeruginosa – and because the toxin is secreted rather than requiring destruction of the cell, the trap can keep on trapping.

Matthew Wook Chang and company take a similar design and extend it two steps farther.   Firstly, they added a method to defeat one of P. aeruginosa’s best defenses, the biofilm.  Because P. aeruginosa biofilms include DNA into the extracellular matrix, they added a secreted DNAse to eliminate the DNA and disrupt the biofilm.  Secondly and perhaps more interestingly, the team retargeted the cell’s chemotaxis system by tying E. coli expression of a chemotaxis regulation protein to the presence of P. aeruginosa’s quorum sensing signal.  This caused the E. coli to gravitate toward P. aeruginosa and release their enzymatic arsenal where it would do the most P. aeruginosa damage.  With this latter addition, then, the waiting trap instead switched over to search and destroy.

This is a really cool idea – an appealing concept in a world that is running out of anti-microbials.  It brought to mind immediately the way the Russians used to use bacteriophages to attack bacterial infections, except these can be designed modularly to strike the right target instead of hoping nature is kind enough to deliver.  One has to wonder how easily it could be used in an infection inside a living system, but a proof of concept can’t be expected to jump that chasm – it’s cool enough that it works at all.  It will be nice, though, to see how readily the approach could actually be adapted to other pathogens and how well it will work clearing infections in vivo.

One also has to wonder, though, if the same idea couldn’t be turned in a different and less pleasant direction.  Could you use it to make a pathogen worse?  Say, could you build a pathogen that used the body’s chemokine and cytokine signals to specifically detect and defeat cells regulating immune responses with chimeric leukocidins or hemolysins or some such?  Beats me, but it feels like something of a goose and gander situation.

(image: Janice Haney Carr/CDC)
Daniel McGown is a first year PhD student in the Biodefense program with a background in molecular microbiology.

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