A different approach to developing new antibiotics

  • A different approach to developing new antibiotics

We are nearing a crisis point in our use (and, sadly, misuse) of antibiotics. Indeed, the World Health Organisation recently described humanity as being in “a race against time” to develop antibiotics against multi-drug resistant superbugs [i]. If we cannot find effective new antibiotics soon, we may be faced with a return to the 1920s pre-antibiotic era, where people routinely died of the most mundane things, like a scratch from a rose thorn while gardening.

A couple of important contributing factors have been the widespread prescription of antibiotics for patients with viral infections, and failure of patients to complete courses of antibiotics once they start feeling better. Because antibiotics don’t work against viruses, the first scenario does nothing to treat disease but does place all of our hundreds of species of natural gut microbes under a “selective pressure”, such that any that evolve the ability to resist the antibiotic will hang around while those around them are killed. Even though these microbes may actually be good for us, bacteria are unbelievably good at passing genes to one another, so new resistance genes may quickly find their way to dangerous disease-causing bacteria. The second scenario, though, provides an even more direct route to dangerous drug-resistant bugs. If we stop a course of antibiotics when only 99% of the disease-causing bacteria have been killed, the remaining 1% – which will include those most naturally resistant to the antibiotics – may come charging straight back at us.

The good news is, we have learned a lot over the past 70 years about how to better use antibiotics to slow the development of resistant bacteria. The bad news is that in that time we have burned our way through nearly all of the antibiotics discovered to date.

Dr Jeremy Owen and I lead a team at Victoria University that is taking two different approaches to try and get new antibiotics into the developmental pipeline. We are particularly interested in molecules known as ‘non-ribosomal peptides’ and ‘polyketides’. These molecules are commonly antibiotics that are made by bacteria to defend themselves against other microbes. They are built inside the bacteria by enzymes – highly specialised little nano-machines that link together to form an assembly line, with each section of the assembly line responsible for adding on a specific part of the antibiotic molecule in a Lego-like fashion (see illustration).

Enzymatic assembly line

The enzymatic assembly lines that make non-ribosomal peptide and polyketide antibiotics are made up of discrete subunits that each play a precise role in recognising and joining different parts of the final product molecule, passing it down the line, and ultimately releasing it. Image credit: JVE Chan-Hyams, modified from DF Ackerley ‘Cracking the non-ribosomal code’ Cell Chem Biol 2016 23(5): 535-7.

One of our team’s approaches is to re-engineer the assembly line in the hope that we can build analogues of existing antibiotics that may get around the resistance mechanisms that disease-causing bacteria have evolved. We have developed approaches to swap out different sections (labelled 1-4 in the Illustration) of an assembly line that makes a particular molecule and replace them with other sections that cause a slightly different ‘Lego part’ to be added into the product molecule. This has been a really fascinating engineering problem, and we have learned a lot about how the assembly lines work, but this line of work is still in its infancy and for now remains a very difficult and inefficient way of making a new drug candidate.

Our more pragmatic approach has been to try and find previously undiscovered antibiotic molecules from nature. The majority of antibiotics in use today were discovered by growing bacteria isolated from different soils around the globe, and testing the different molecules they naturally secrete. From the 1940s to 1960s this was a highly productive approach, but thereafter researchers struggled to find anything new – the same sets of molecules just kept cropping up time and time again. In recent times we have realised that only a very small proportion of soil bacteria – under one percent! – can be grown effectively outside of their natural environment. It is therefore extremely likely that the remaining 99% produce some very effective antibiotics that we have previously been unable to access.

To get around the problem that we cannot presently grow most soil bacteria in the lab, we instead go straight to their DNA, purified directly from the soil. We have developed and optimised several different strategies to ‘fish out’ clusters of gene that encode the types of assembly line pictured in the Illustration. These effectively act as blueprints that tell a cell how to make one particular antibiotic. Taking advantage of the fact that bacteria are so good at swapping bits of DNA, we and others have shown that you can transfer these blueprints to a new host – a bacterium that we can grow in the lab – and a surprising amount of the time it will gain the ability to produce a new antibiotic! Luckily for us, most antibiotic gene clusters not only encode the assembly line needed to make an antibiotic, but also a means for defending the host cell against any toxic effects.

This is still a new line of research in New Zealand, but before he returned home in 2015, Jeremy successfully used similar approaches at The Rockefeller University in New York. There he discovered, produced, and tested a number of previously unknown molecules, including novel antibiotics and compounds with anti-cancer potential (see paper one and two on the Proceedings of the National Academy of Sciences USA. We already have indications that NZ soils are rich in equally promising new drug candidates, and are working hard to pull some of those out. However, rigorous testing standards mean that even if we do find new antibiotics that work well in people, it will likely be at least ten years before any of these enter clinical use. Nevertheless, it is critical to keep the discovery pipelines flowing if we are to avert the crisis foreseen by the World Health Organisation and numerous other medical organisations around the globe.

[i] Bulletin of the World Health Organization 2011;89:88–89. doi:10.2471/BLT.11.030211

Associate Professor David Ackerley and colleagues from Victoria University Wellington recently featured on the cover of a leading international journal with an image of bacteria grown in the shape of New Zealand. The cover related to their work investigating the potential of engineering improved antibiotics.


About

Associate Professor David Ackerley is from the School of Biological Sciences at Victoria University Wellington. A major theme of his research is directed evolution, artificial acceleration of rates of mutation and recombination in genes and genomes, and selection of variants with improved qualities. David is also an Associate Investigator for the Maurice Wilkins Centre of Molecular Biodiscovery.


What is InfectedNZ?

Hey, Aotearoa. It’s time we had a chat about infectious diseases and what we’re going to do about the looming antimicrobial armageddon. That’s why we’ve asked leading health, social and economic researchers, and people with personal stories, to help us get real about our vulnerability and discuss solutions. Follow their blogs right here at tepunhahamatatini.ac.nz and watch the conversation spread across social media with #infectedNZ.

Backing it all up, wherever possible, is data from the good folk at Figure.NZ. Their super duper charts are based on data sourced from public repositories, government departments, academics and corporations. Check out their #infectedNZ data board and sign-up to create your very own data board on any topic that floats your boat.

Leave a reply

Your email address will not be published. Required fields are marked *