Antibiotics Target Gene Expression

This week, the British government's Chief Medical Officer, Dame Sally Davies called for antibiotic resistance to be treated as a major national risk on par with climate change or terrorism.  To find out about a new type antibiotics that could reduce bacterial resistance, we were joined by Michael McArthur, the Chief Scientific Officer of the research company, ProCarta BioSystems. 

Kat -  What's different about the antibiotics that you're developing from the traditional antibiotics that we're rapidly running out of?

Michael - Well, traditional antibiotics go after only a limited set of targets. And you're right, that resistance mechanisms now are embedded in the clinic. So, it's very difficult to circumvent them now. So, our approach is to target entirely new therapeutic targets, which is gene expression. Bacteria need to turn on certain genes in order to survive inside the host, in order to become pathogenic. And by using simple oligonucleotide switches that are rationally and easily designed, we've been able to show in vitro and in vivo that we can stop these genes from being expressed and therefore, defeat infection. And that's important also because it's a genuine platform technology. We can anticipate making a whole series of antibiotics against a series of different pathogens rather than relying on a new discovery to find a new molecule and pairing it with a particular infection.

Kat - So, the idea is that the antibiotics are actually these little stretches of nucleotides, these little stretches of kind of complimentary DNA that you would give those to people.

Michael - That's right. We call them transcription factor decoys and that's what they do. They mimic the binding sight of the transcription factors that would normally control gene expression. These transcription factors now bind to the decoys and we therefore, in that way, control gene expression.

Kat - And is this for just particular genes in the bacteria like the ones that make them grow or if you just target any genes, you'll just knacker the bacteria?

Michael - We choose our targets carefully so we can choose them, so there are narrow spectrum which is to say we can defeat specific infections like C. difficile without causing damage to the commensal bacteria - the good bacteria in your gut. Or we can design sequences for the very broad and defeat a wide class of bacteria like the gram negatives. So, it really puts us in-charge of determining the specificity of antibiotics and I think that's going to be important as we learn more about how to use antibiotics properly in the future.

Kat - Now, I know that there's other types of diseases where people are looking at trying to use these very short stretches of nucleotides, but it seems to me at the moment that there's a problem with actually delivering them really effectively to get into the right places in people's bodies in the right doses. Is this a challenge that you're coming up against?

Michael - It's a challenge we've had to overcome. So, we have a proprietary delivery system which allows us to deliver these decoys right in the heart of bacteria. We found a lipid which can encapsulate the oligonucleotide and form a nano particle, a small...

Kat - Sort of a fatty little bubble basically.

Michael -  A fatty little bubble, yes which is a rather interesting and unique property that it can crossover bacterial membranes to get inside the cell.

Kat - Because these things are really impenetrable bacteria. I mean, that's partly why they're so successful.  You just can't get anything in them.

Michael - Well, certainly several drugs have failed because they can't get into bacteria, but if you do make them membrane-like then yes, you can trick the bacteria and they get taken up readily. And then you can choose bacterial infections which occur either on skin or in the blood.  So, it's not like we have to target them to liver cells. We can actually choose our infections which are more readily accessible for us.

Kat - So, where is this research at the moment? Is it just on bacteria growing on petri dishes in the lab or you're hoping to take it into humans?

Michael - Well, we've announced today that we're taking our lead programme which is a MRSA programme and it's the first product that we foresee. We're looking at topical applications, looking at nasal decolonisation. Staph areus grows naturally in your nose and if you can get rid of that and perform a major surgery then that's a great advantage and helps recovery.

Kat - So, some kind of presurgical nose spray basically.

Michael - That's right and that's the first step for the company and then we see further products around Staph areus as an intravenous drug. But we're following up also with C. difficile products and products to defeat gram negative infections which are the really big challenge out there.

Chris - Can I just ask because one of Dame Sally Davies's points is that we're seeing enormous amounts of antibiotic resistance. So, what is to stop the bugs becoming resistant to the challenge or the gaunt that you're throwing down with your new antimicrobial strategy?

Michael - Well partly, it's because our system is so adaptable. So, if we do see resistance arising, we have other targets we can go for and simply by making rational changes, the oligonucleotide sequence, we can get around any resistance mechanism that comes up at the level of transcription. The delivery system seems to be very robust, so we've tested that against a whole panel of clinical isolates. We haven't found one yet that it can't get into, so I think there is hope there. There's nothing that's going to be resistance proof and I think in the future, we're going to be looking at better stewardship of antibiotics. More considerate use, marrying it with better diagnostics, and that's going to be part of the solution as well.

David - I was just wondering. You mentioned that different bacteria within the gut, so you've got these healthy and these sort of unhealthy bacteria and you can target specifically unhealthy bacteria. So, is there any idea whether the human immune system is going to be susceptible to these oligonucleotides or is it definitely very specific just to bacteria?

Michael - We can use bioinformatics to make sure that the sequences should only affect bacterial gene expression patterns, but we do see a great role for our technology as a genuine research tool to try and unpick that relationship between gut microbes and the human immunogenic reaction. I think that's going to be a very interesting area of our research as well.