Discovering Drugs from Bugs

20 July 2008

Interview with

Melanie McCullagh, Biotica Technology

Chris - Welcome Melanie, thank you for joining us.  What are you actually up to?

Melanie - Yes, Biotica has a technology which I would say is quite the other end of the spectrum from Astex.  Polyketides that are a type of compound produced naturally in soil bacteria.  A lot of them are very naturally pharmaceutically active as well.

Chris - What are they?

Melanie - They're fairly large molecules.  They're around 500
Daltons and they are made up of a series of carboxylic acids which are joined together in the bacteria by an enzyme called polyketide synthase.

Chris - What do they do?

Ball-and-stick model of sirolimus (rapamycin).Melanie - Well, we're not completely sure what they do necessarily within the bacteria.  We don't know why they produce them per se but when we give them to humans they interact with a really wide range of targets.  Some of the really famous examples, for example rapamycin, is an immunosuppressant.   It's used in transplant patients to prevent them rejecting the organ that's been given.  There are also analogues of rapamycin which are used in cancer, for example.  It's been used and tested in other indications as well.  They're more broadly applicable than that.  There are antibacterial polyketides such as erythromycin.  Some of the early anti-cholesterol statins were also polyketides and they're also used in cancer. Some really novel cancer compounds which have been recently approved are also polyketide compounds.

Chris - What you're saying is that bacteria have a pretty broad medicine chest at their disposal. All we have to do is to work out how to get it out.

Melanie - Yes, that's right.

Chris - What are you doing to do that?

Melanie - Biotica specialises in genetically engineering the bacteria so that we can change the properties of the polyketides that are naturally produced. One really good example is there's a polyketide called FK506 which is an immunosuppressant. It's used in transplant patients. What we're doing is working on that molecule to change its pharmaceutical properties, make it appropriate for delivering for example by inhalation. We can then take advantage of the fact that it down-regulates inflammation, down-regulates the immune system and give it to asthma patients. The interesting thing about FK506 is that when it's given systemically it's quite toxic. It has very variable metabolism. What we can do it we can change the metabolism of the drug to make it more appropriate to give in a bigger indication like asthma, really reduce the toxicity of that molecule. DNA

Chris - How do you how to tweak the DNA of the bacteria so that they make a different molecule which is more human-friendly?

Melanie - The polyketide synthase is a very interesting enzyme. The genes directly translate to different molecules within the polyketide synthase. Each of those will produce carboxylic acid and may change the acid as it's added onto the polyketide. By looking at the genome with the bacteria we can actually identify how to change the individual modules within the polyketide synthase. For example, we can swap from one organism to another to recruit different acids into a polyketide molecule. We can tell by looking at the structure and activity relationships of the molecules that we know we can tell what changes we have to make to make changes in the activity of the molecule within the human.

Chris - Is anyone else doing this or is this your unique selling point?

Melanie - Biotica has patents on this technology. We're the only company who is able to do certain parts of the technology. There are other companies that are doing similar things, perhaps with different types of molecules. There was another company who had some other kind of overlapping technology in the US which has recently been bought by one of the very big pharmaceutical companies.

Chris - So the bottom line here is that, rather than taking the molecule and fiddling with it chemically, you can actually take a molecule that the bacteria are already making, fiddle with the bacteria and make them make it better?

Melanie - We can get the bacteria to do the work for us. The bacteria also produce the molecules commercially as well. We can scale-up, ferment lots of bacteria and get pharmaceuticals out really efficiently.

Chris - Because bacteria don't charge a salary and they don't get bogged in health and safety?

Mario - Is it possible to create an intelligent vaccine or a drug that could evolve with the ever changing strains of the disease?

Melanie - That's a very interesting question. I'm not sure that you would actually want a vaccine to evolve too much just in case once you set it loose in the wild you would risk some kind of a vaccine epidemic. I think what you can definitely do is apply selection pressure to the bacteria to change the types of molecules that they produce. That's a similar kind of concept.

Chris - I would think that probably this is going to be big business in the future. We're only just beginning to understand how molecules actually look. By turning this round in this way we can now start with what we want to end up with and then go back to the gene and tweak that. That's quite a novel thing to be doing. Probably going to be a major way of doing this in the future.

Melanie - There are some real advances in technology at the moment that I think will enable us to expand greatly what we can do with genetically engineering the bacteria that produce these polyketides. Biotica's a very small company but I think there's a really big area for us to build into with increasingly novel technologies as things move on.

Add a comment