New class of antibiotics discovered

Can we solve the threat of antibiotic resistance by learning more about the structure of bugs?
04 August 2014

Interview with 

Neil Paterson, Diamond Light Source


The beamline at Diamond


The World Health Organization (WHO) estimates that antibiotics add an averageThe beamline at Diamond of 20 years to all of our lives. But since the discovery of penicillin in 1928, overuse of these drugs has led bacteria to evolve resistance, meaning certain superbugs - like MRSA and tuberculosis, are becoming untreatable.Scientists are trying to solve the problem by learning more about the structure of bugs themselves in the hopes of finding a new chink in their armour that we can use to attack them. Dr Neil Paterson works at Diamond and he told Ginny Smith about a new class of antibiotic....

Neil -   The main difference with the antibiotic target we've discovered is that it's located on the very outer surface of the bacterial cell.  So hopefully, any new drugs that target this won't have to cross the cell membrane and enter the cell.  And therefore, they're not subject to detoxification by proteins inside the organism or the the efflux pumping which is one of the major mechanisms for bacterial resistance.

Ginny -   So, when you detoxification, what do you mean?  What are the bacteria actually doing when they evolve resistance to normal antibiotics?

Neil -   The main aim of the bacteria is to keep the level of drug below lethal concentration.  So, they can achieve that either by binding the drug and preventing it getting to its target protein or they could bind the drug and change its chemical structure, or they could pump it back out.  Bacteria have to deal with toxic compounds in their environment on a regular basis.  They have these pumps that pick up a wide range of compounds that the cell doesn't want to have inside and they pump it straight back out.  That just prevents the concentration reaching a lethal level.

Ginny -   How does your new target solve those problems, get around those issues?

Neil -   Well, it's located on the very surface of the cell.  So, this is the part of the organism that's directly exposed to the host.  For it to function, it needs to open up and allow the passage of a lipopolysaccharide molecule and that's a molecule that decorates the surface of a bacterial cell.

Ginny -   Could we try and simplify the language a bit because you're throwing quite a few big words out there that I think I'm getting a bit lost and I think our listeners certainly will be?  So, if you could just try and avoid using technical terms as much as possible?  Should we go back to the beginning of that question?  Is that alright?

How does your target solve those problems and avoid being caught up by those mechanisms?

Neil -   Well, our target is located on the very surface of the bacterial cell.  And because it needs to open to perform its function, we have an opportunity there to interact with that protein without the drug having to enter the cell in the first place.

Ginny -   What does it actually do to kill the bacteria?

Neil -   So, the protein we've solved the structure of, it's a pore.  So, if you imagine a tube a bit like a piece of toilet roll holder, slightly squeezed and it sits within the surface of the spherical cell with an opening at either end.  Now, what we've actually solved is a protein complex.  So, there are two proteins in there.  One sits inside this tube and this protein complex performs the final step in assembling the outer surface of a bacteria.  It transports a large molecule through the pore in the centre and then it serves it into the outer side of the outer membrane.

Ginny -   So, if you prevent that from working, then the bacteria kind of can't build its coat?

Neil -   It can't build its coat and it can't survive.

Ginny -   How has Diamond helped you in discovering that protein?

Neil -   Proteins are very small.  So, the protein we've solved the structure of is approximately 100,000th of a millimetre.  What Diamond gives us is, it gives us very intense x-rays which is the sort of wavelength we need to be able to visualise something that small. 

One of the main problems we have, of course, is that biological material and x-rays don't really work well together.  You get a lot of radiation damage.  And because of that, we have to encourage the protein to form a crystal so that we can spread that damage out across many copies of the protein.

Ginny -   When you say crystal, what exactly do you mean?  I mean, I'm thinking of a grain of salt here.  Is  that kind of what it looks like?

Neil -   It looks very similar actually.  All crystals are essentially repeating subunit.  So, you have lots of copies of a certain thing, all arranged in the same manner and then built together like lego blocks.

Ginny -   So, are there any drugs being developed using this new method?

Neil -   Yes.  A group in Switzerland have discovered that if they modify a naturally occurring antimicrobial agent, and that molecule is used by mammalian cells to kill bacteria.  It looks like a bit like a hairpin and it inserts into the outer membrane.  When it reaches a certain concentration, it forms a pore and spills cell contents.  What they found is if you modify that, it no longer forms a pore, but it's still lethal.  They discovered that it binds to the pore part of the complex we solved the structure of.  Now, they've developed that a bit further prior to us, providing the protein structure.  And they've got a compound in phase 2 clinical trials that's active against pseudomonas aeruginosa, an opportunistic lung infection.  So, what we've provided in there was a structure of the target and hopefully, we can use that to understand how their drug works, how to perhaps allow it to be effective against other gram negative bacteria.

Ginny -   So, if this is an entirely new class of antibiotics, does that mean we can stop worrying about antibiotic resistant bacteria?

Neil -   Definitely, not.  Bacteria in common with the other microorganisms have been engaged in chemical warfare for millions of years.  When you look at the penicillins, they were originally from a mould that's used to kill bacteria that were competing for its nutrients. 

What a new class would buy us is a good few decades probably of safety, if we're smart with the use of those compounds, we might be able to extend that further. 

Ginny -   Thanks, Neil.  Dr. Neil Patterson from Diamond.


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