And then we started to look at other bacteria, and these are just a smattering of the molecules that we’ve discovered. What I hope you can see is that the molecules are related. So the left-hand part of the molecule is identical in every single species of bacteria. But the right-hand part of the molecule is a little bit different in every single species.
And what that does is to confer exquisite species specificities to these languages. So each molecule fits into its partner receptor and no other. So these are private, secret conversations. These conversations are for intraspecies communication. Each bacteria uses a particular molecule that’s – its language that allows it to count its own siblings.
And so once we got that far we thought we were starting to understand that bacteria have these social behaviors. But what we were really thinking about is that most of the time bacteria don’t live by themselves, they live in incredible mixtures, with hundreds or thousands of other species of bacteria. And that’s depicted on this slide. This is your skin.
So this is just a picture — a micrograph of your skin. Anywhere on your body, it looks pretty much like this, and what I hope you can see is that there’s all kinds of bacteria there.
And so we started to think if this really is about communication in bacteria, and it’s about counting your neighbors, it’s not enough to be able to only talk within your species. There has to be a way to take a census of the rest of the bacteria in the population.
So we went back to molecular biology and started studying different bacteria, and what we’ve found now is that in fact, bacteria are multilingual. So they all have a species-specific system — they have a molecule that says “me.” But then, running in parallel to that is a second system that we’ve discovered, that’s generic.
So, they have a second enzyme that makes a second signal and it has its own receptor, and this molecule is the trade language of bacteria. It’s used by all different bacteria and it’s the language of interspecies communication.
And so what happens is that bacteria are able to count how many of me and how many of you. And they take that information inside, and they decide what tasks to carry out depending on who’s in the minority and who’s in the majority of any given population.
And so then again we turned to chemistry, and we figured out what this generic molecule is — that was the pink ovals on my last slide, this is it. It’s a very small, five-carbon molecule. What the important thing is that we learned is that every bacterium has exactly the same enzyme and makes exactly the same molecule. So they’re all using this molecule for interspecies communication. So this is the bacterial Esperanto.
And so once we got that far, we started to learn that bacteria can talk to each other with this chemical language. But what we started to think is that maybe there is something practical that we can do here as well.
So I’ve told you that bacteria do have all these social behaviors, that they communicate with these molecules. And of course, I’ve also told you that one of the important things they do is to initiate pathogenicity using quorum sensing.
So we thought, what if we made these bacteria so they can’t talk or they can’t hear? Couldn’t these be new kinds of antibiotics? Of course, you’ve just heard and you already know that we’re running out of antibiotics. Bacteria are incredibly multi-drug-resistant right now, and that’s because all of the antibiotics that we use kill bacteria. So they either pop the bacterial membrane, they make the bacterium so it can’t replicate its DNA. We kill bacteria with traditional antibiotics and that selects for resistant mutants. And so now of course we have this global problem in infectious diseases.
So we thought, well what if we could sort of do behavior modifications, just make these bacteria so they can’t talk, they can’t count, and they don’t know to launch virulence. And so that’s exactly what we’ve done, and we’ve sort of taken two strategies.
The first one is we’ve targeted the intraspecies communication system. So we made molecules that look kind of like the real molecules — which you saw — but they’re a little bit different. And so they lock into those receptors, and they jam recognition of the real thing.
And so by targeting the red system, what we are able to do is to make species-specific, or disease-specific, anti-quorum sensing molecules. We’ve also done the same thing with the pink system. We’ve taken that universal molecule and turned it around a little bit so that we’ve made antagonists of the interspecies communication system. The hope is that these will be used as broad-spectrum antibiotics that work against all bacteria.
So to finish I’ll just show you the strategy. In this one I’m just using the interspecies molecule, but the logic is exactly the same. What you know is that when that bacterium gets into the animal, in this case, a mouse, it doesn’t initiate virulence right away. It gets in, it starts growing, it starts secreting its quorum sensing molecules. It recognizes when it has enough bacteria that now they’re going to launch their attack, and the animal dies.
And so what we’ve been able to do is to give these virulent infections, but we give them in conjunction with our anti-quorum sensing molecules — so these are molecules that look kind of like the real thing, but they’re a little bit different which I’ve depicted on this slide. What we now know is that if we treat the animal with a pathogenic bacterium — a multi-drug-resistant pathogenic bacterium — in the same time we give our anti-quorum sensing molecule, in fact, the animal lives.