A Blog by Ed Yong

Scientists engineer suicide bomber bacteria to kill other bacteria

In a lab in Singapore, scientists are designing and breeding suicide bombers. If their efforts pan out, they will be applauded rather than jailed, for their targets are neither humans nor buildings. They’re bacteria.

Nazanin Saeidi and Choon Kit Wong have found a new way of killing Pseudomonas aeruginosa, an opportunistic species that thrives wherever humans are weak. It commonly infects hospital patients whose immune systems have taken a hit. It targets any tissue it can get a foothold on – lungs, bladders, guts – and it often causes fatal infections. To seek and destroy this threat, Saiedi and Wong have used the common lab bacterium Escherichia coli as a sacrificial pawn.

Their E.coli recruits produce a protein called LasR, which recognises molecules that P.aeruginosa cells use to communicate with one another. When LasR detects to these chemical signals, it switches on two genes. The first one arms the bomb. It produces pyocin, a toxin that kills P.aeruginosa by drilling through its outer wall and causing its innards to leak out. The second gene detonates the bomb. It produces a protein that causes the E.coli to burst apart, killing itself but also releasing a flood of deadly pyocin upon nearby P.aeruginosa.

The beauty of this solution is that it uses P.aeurginosa’s own weapons against it. Pyocins are actually a P.aeruginosa innovation. When times are tough, these opportunists use pyocins to kill off competing strains. Saeidi and Wong focused on one of these weapons – a pyocin known as S5. It comes in two parts: one does the killing; the other makes the host cell immune to its own weapons. By arming their bombers with pyocin S5, Saeidi and Wong found that they could kill many P.aeruginosa strains that cause problems for hospital patients.

In preliminary lab tests, the E.coli bombers proved to be remarkably effective against P.aeruginosa. When the two species were mixed together, the bombers took out around 99% of their targets. They even killed around 90% of cells in slimy communities of P.aeruginosa called biofilms. Biofilms are like bacterial cities and they are notoriously hard to destroy. The E.coli bombers levelled them.

Of course, Saeidi and Wong’s method is a long way from actual clinical use. They haven’t even tested their suicide bomber bacteria in a live animal yet, much less in human patients. This is merely a proof of principle. Even so, it’s hard not to get excited about scientists exploring ingenious new ways of tackling infectious bacteria. We are, after all, losing the war against such microbes.

The development of new anti-bacterial drugs has ground to a halt. The vast majority of antibiotic classes were created between the 1940s and 1960s, with only two new ones entering the market in the last decade. Meanwhile, bacteria have been evolving resistance to current arsenal, and people have already documented strains that resist virtually all of our known drugs.

P.aeruginosa is particularly hard to treat because it’s already naturally resistant to a large variety of antibiotics. It has a number of molecular pumps that evict any drug that gets inside it. Doctors often try to treat it by hitting it with a number of different drugs, but it can shift to a dormant and tolerant state, where it survives by keeping its head down. Meanwhile, the drug onslaught harms helpful bacteria that normally colonise our bodies.

As an alternative, some scientists have tried using viruses called phages, which target and kill bacteria. They’ve had some success in mice but Saeidi and Wong think that this approach has problems. It can only be used once – after that, the host developed antibodies against the viruses.

Saeidi and Wong have taken a different approach. Their work is an example of the exciting field of synthetic biology, where scientists tweak biology to perform tasks that their natural counterparts cannot. Often, this involves knitting together natural components in new combinations, like picking parts off a shelf to create custom-built living things. In this case, Saeidi and Wong connected the genetic components for recognising P.aeruginosa, creating pyocin and committing explosive suicide, so that the first event would trigger the latter two.

The field has produced some amusing parlour tricks as well as more useful achievements, including using bacteria and fungi to make antimalarial drugs, create biofuels, decontaminate water and even hunt cancer cells. But until now, no one has tried to send bacteria after their own kind. Saeidi and Wong’s study may be preliminary, but they have blazed a fresh and intriguing trail.

Reference: Saeidi, Wong, Lo, Nguyen, Ling, Leong, Poh & Chang. 2011. Engineering microbes to sense and eradicate Pseudomonas aeruginosa, a human pathogen. Molecular Systems Biology http://dx.doi.org/10.1038/msb.2011.55

11 thoughts on “Scientists engineer suicide bomber bacteria to kill other bacteria

  1. In living hosts, they’re going to have to get around the obstacle of the host immunity targeting and eliminating the E. coli.

  2. @Preston – bit of both. Look at a burst cell under an electron microscope and it basically looks like a popped water balloon with dark matter flowing out from in.

    @Amphiox – Surely E.coli is a common enough commensal that this isn’t really a big problem.

  3. Intriguing and exciting but I wonder how long before P.aeruginosa adapt to use different molecules to communicate with one another that LasR won’t detect.

  4. @Ed-E. coli is a common commensal but that doesn’t mean that it wouldn’t be targeted by host immune processes. E. coli leakage from the gut for example elicits a response, as does E. coli in the bloodstream.

    However, the bigger picture here is that patients with significant Pa infections usually don’t have sufficient immune systems to properly deal with invading pathogens anyway (e.g. CF patients don’t tend to mount good responses in lungs which is why Pa films flourish there in the first place).

    Additionally, could you provide some links to papers demonstrating “It can only be used once – after that, the host developed antibodies against the viruses”. I’m curious if any of those works were performed in immune-suppressed animals (the nature of Pa infections suggests that most Pa patients would be immune-suppressed in some manner, i.e. burn, trauma, sepsis, CF, etc); I could understand though how that might be an issue in healthy individuals. The reason I ask is that I have a feeling that having all those PAMPs floating around in sensitive tissues would be a bad idea (SIRS and shock risks) and I tend to think that phage would be a safer route.

  5. This is incredibly exciting for CF patients like me. Almost all CF patients eventually come down with chronic P. aeruginosa, and there aren’t too many treatment options. I keep my infection “down” with inhaled Tobi, taken via nebulizer. But when flare-ups occur, I get a PICCline IV with liquid Tobramyacine. Fun!

    I’m entering a drug study for something called M-Pex, which is a similar type of inhaled solution but it doesn’t take as long and is supposedly more effective than inhaled Tobi. Still, any news of a new weapon against Pa is pretty awesome. I’ll have to ask my doctor about this and see what he thinks of it.

    Thanks for the head’s up, Ed!

  6. @Ed, I’m with Drew on this one, sure, E. coli is a commensal, but Pseuds are also commonly found everywhere as well (its a very common soil bacteria), I’m sure most of us come into contact with it daily. Pseuds usually cause opportunistic infections in immuno-compromised people such as CF patients or post-surgery patients and healthy individuals are usually safe from it.

    I agree that “some” of the virus in phage therapy will be eliminated by our host immune system but not all of them, there are viruses which are designed with human protein coating (camouflage of sorts) which will trick the host immune system into recognizing it as a host cell, it could then proceed to do its work in targeting its cell of interest. These viruses are currently used in a lot of phage therapy studies in targeting bacterial cells and also host cells in counteracting genetic diseases.

    Another aspect of this study is the reliance of the expression of pyocin towards LasR, which is one of the quorum sensing molecules in Pseuds. LasR is used by bacteria to control their gene expression under the influence of cell-population density. It enables the coordination and synchronization of the activities of a large group of bacterial cells in an environment such as a biofilm. So LasR is required in a large concentration to be able to trigger the production of the pyocin in the E. coli and for that the researchers must make sure that the E. coli must travel to the site of infection (biofilm) in order for the E. coli to work its magic.

    Besides that, we wouldn’t know what will happen to the E. coli after it enters our body, will it travel to the site of infection? Will it cause a drastic change in our gut microflora which will lead to other unforseen infections? Moreover, the pyocin released during the lysis of the E. coli might also be a concern as it might trigger an immune response as well, so there are still lots to think about in the in vivo aspect of this study.

    There are still a lot more factors to consider besides the ones I’ve mentioned here before an in vivo study could be carried out as it is not as straight forward as it seems. But it is still a step forward in our battle against antibiotic resistant bacterias.


  7. This is dangerous research. The outcome is hard to predict.

    What happens if the suicide bacteria attack beneficial bacteria in our gut or the gut of cows.

    All we need to do is to look at how Monsanto’s gene has migrated to understand the potential for this to get out of hand.

  8. this is definitely some exciting genetic engineering! However, you are killing two Gram-negative bacteria, Pseudomonas and E. coli. Depending on the concentration of both bacterial populations, endotoxic shock in your patients would definitely be a concern I would think besides what Jeremy said about pyocin mediated inflammation.

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