Triggering tuberculosis to self-destruct

26 February 2019

Interview with

Andres Floto, Cambridge University


A suicide switch that triggers the bacteria that cause TB - tuberculosis - to kill themselves has been uncovered by scientists in France. The discovery could enable scientists to develop a new class of antibiotic drugs that can trip this switch and cause the bacteria to die. This would also be a big help in combating the problem of antibiotic resistance. Respiratory specialist Andres Floto, from the University of Cambridge, who wasn’t involved in the research itself, took Chris Smith through the findings…

Andres - This group's been interested in understanding how to kill mycobacteria in tuberculosis, which is what causes TB, and what they focused on is a toxin-antitoxin system. This is a strategy that's used by lots of bacteria where they produce a poison, and at the same time produce an antidote. And what that means is that other bacteria that don't have the antidote will die. So what this group have found is that one of the toxin-antitoxin systems can be manipulated, meaning if you block the antitoxin then the bacteria die - and they've proposed that this is an exciting new way to kill tuberculosis.

Chris - So what... We would make some kind of drug molecule that would either activate the toxin or deactivate the antitoxin, so we push the bugs into, basically, committing suicide?

Andres - Absolutely. So the idea is by solving the structure of both the toxin and the antitoxin, understanding how they bind and neutralize each other normally, you can imagine that structure-guided development of a small molecule could block that interaction, allow the toxin to remain active and allow, as you say, the bacteria to commit suicide.

Chris - So this is - when you say ‘structure’ - the three-dimensional structure where the atoms are in three dimensional space, essentially?

Andres -  You're exactly right. It’s a three-dimensional structure and it's done by looking at crystals with x-rays. But once you've got that structure, you can see exactly where each atom is and how to block interactions.

Chris - And how did they uncover this in the first place?

Andres - They sequentially knocked out all of the genes in TB and asked the question: “which genes were essential?”, and it turns out that they’d knocked out one of the antitoxin pairs and by knocking out the antitoxin it allowed the toxin to remain unneutralized and hence the bacteria killed. So once they realized that this toxin-antitoxin system was so potent if you neutralized the antitoxin, they proved that if you induce the expression of the toxin on its own without the antitoxin, you kill the bacteria. They did that in liquid culture and perhaps most impressively in mice.

Chris - And that means that the strategy is sound to try to then activate such a system as a means of persuading these microbes to kill themselves?

Andreas - Right. It's a proof of concept experiment. I think the hard work now is to develop antibiotic-like molecules that can do this in real life.

Chris - Do they know how the toxin persuades the microbe to kill itself? Because that's another interesting part of the story, isn't it? Because if you can not just understand the toxin but also understand what lies downstream of it, you could plug into that downstream system to kill it too?

Andres - Yeah. So TB, like all organisms, relies on metabolism - that's the breakdown of nutrients in order to make energy. And one of the key components of that is this molecule called NAD. And what they found was that this toxin splits NAD and inactivates it and effectively starves the bacteria into death. So you're right, this is a really exciting mechanism of action for the toxin, and again may open up new avenues for new drugs.

Chris - Do we have anything that looks like it could be a candidate to do that? Because that molecule you mentioned, NAD, is it's ubiquitous in life isn't it? Many many systems use that, So by going after it, could we end up with a drug with lots and lots of side effects?

Andres - Yeah. So I think that's absolutely right. I mean, the beauty of the toxin is it seems to be specific for bacteria. They did quite a lot of studies looking at human cells and didn't really find an increase in toxicity in the human cells. Now that's very different from proving that it's safe, but it does kind of suggest that this may be a very neat specific way of killing tuberculosis.

Chris - And will it be specific just for Mycobacterium tuberculosis - what we call ‘human TB’? Because, obviously, if you wind the clock back, there are lots of humans who caught TB from cows - Mycobacterium bovis, its relative. Can it target more than just TB?

Andres - Yeah, no. So, in theory, this should be applicable across all mycobacterial species. There’s about 160 species that infect other animals, or in the environment and occasionally infect vulnerable people. And it may also have effects on other bacteria, so, more distant species of bacteria. So it's potentially very interesting

Chris - Because TB, not to put too fine a point on it, is a massive international scourge and getting worse isn't it?

Andres - It's a huge problem. I mean, the estimates are that about a third of the population have been exposed to TB at some point. There’s something like 10 million or so cases a year of TB, about 2 million deaths... so it's a big problem. There's been huge efforts and a lot of success, actually, in controlling TB. The big problem now is multi-drug resistant TB which is running at about half a million cases a year and is a real headache.


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