Digging for Antibiotics
Paul - Well, there's been a lot of interest in why microbes make antibiotics, over a long period of time. The soil where they live is a very complicated environment and there are lots of competitor organisms there, so they have to compete with other bacteria, with fungi, with protozoa and also, higher organisms like nematodes. So, one of the ways that they can do this is by giving themselves a competitive advantage. So by producing compounds that can perhaps kill these competitors or signal to those competitors that they need to leave the area where there's a resource that they like to defend, and this is how Streptomyces and the related Actinomycete bacteria try and defend the nutrients that they live on. They are primary degraders of lots of dead leaves, and dead insect carapaces within the soil, so it's really about defending any available nutrients in the soil.
Sarah - And how do they actually go about making them? What's the process?
Paul - So, the process is incredibly complicated. In simple terms, they have large arrays of genes that we call biosynthetic clusters that you find within their genomes. They take primarily carbon and some nitrogen molecules and they assemble these into very complicated chemical structures which are made within the cells, and then they excrete them out into the environment to act on the competitor organisms. This can be over a range of chemical classes, some of them incredibly complicated and representing huge molecular masses.
Sarah - And I'm guessing, because they're so complicated that that's why we go looking for them in bacteria and we don't try and synthesise them ourselves in the lab.
Paul - Yeah, absolutely. These chemical structures are often very difficult to make using synthetic organic chemistry and actually, over millions of years of evolution, these organisms have developed the chemistry and enzymes which can do these reactions very efficiently and very quickly. So, the pharmaceutical factories are already out there in the soil, so we may as well go find them.
Sarah - I suppose also though they're not just producing these chemicals to sort of tell other microbes to get lost from their food source? They're also doing all kinds of other processes as well. How do we optimise it when we make these things, when we use these bacteria ourselves? How do we optimise it so that they are just making the chemicals that we want and not making all these other things that we don't necessarily find useful?
Paul - So, we've looked for many strains over, probably the last 60 or so years, and we often find a strain that makes one particular product very well, and that's easy to then transfer into liquid culture and scale up into big fermentations where the organisms secrete it into the media and then we can just harvest the media and purify the antibiotics from that. More recently, what's happened is, since we've been sequencing genomes of these organisms, we've actually found the genes to make lots of other compounds and there's a lot of interest now in how we can perhaps harness the power of those hidden clusters and activate them, and start to identify new antibiotics in that way.
Sarah - And if you're able to then use these genes in perhaps other microbes that are easier to culture, does that reduce the worry that you might also get contaminants going on in there as well?
Paul - Well, I mean, these organisms are generally saprophytic organisms, they live on dead leaves and don't cause any pathogenecity so that the fermentations are incredibly safe and represent very little in terms of pathogenic threat. But often, they're very slow growing organisms because they live in the soil and resources are scarce. They don't need to grow quickly. So for example, everybody knows that an organism like Escherichia coli can double every 20 minutes or so under optimum lab conditions. For some of the Streptomyces, this may be in the region of 4 to 12 hours for the doubling time. So really, what we do is we try and move these biosynthetic clusters for antibiotics into strains so they grow a little bit quicker or can perhaps make more of that product.
Sarah - And could we just go out into our back gardens and dig up a trowel full of soil and it would have the type of useful Streptomyces bacteria that you're looking at?
Paul - Absolutely. The antibiotic Streptomycin which is very famous for being the first antibiotic active against Mycobacterium Tuberculosis - the organism that causes TB - is one of the commonest Streptomyces that you can isolate and you get maybe 10 million Streptomyces griseus spores in every gram of soil in virtually every environment we've looked in.
Sarah - So, have we found everything there is to find or is there still more out there, do you think?
Paul - There are lots of organisms still out there. There's a lot of interest now in exploring unusual niches such a hyper-arid soils from deserts such as the Atacama Desert, which is as an area of particular interest at the moment. But also looking in muds and silts at the bottom of the ocean, and lots of really good compounds have been found there recently with some having anti-cancer activities as well.
Sarah - One of the main worries with antibiotics is the problem of resistance. If these chemicals are already existing in soil and already interacting with other microbes, is there the danger that's there's already a level of resistance there that could spread to humans?
Paul - Well, resistance is a bit like taxes. It's inevitable. Because these organisms have been around for 400 million years, living in the soil, interacting with all the soil organisms, because they produce these compounds, they have to also be resistant to their own compounds. So many of antibiotic resistance genes that we see in the clinic probably have their origin in Streptomycete-like bacteria.
There's been some work from a lab in Canada recently by Jerry Wright where they've looked in caves that have never had any human activity in there and they still find antibiotic resistance genes out there that are still relevant in the clinic. So, resistance genes are out there and resistance will be inevitable. We need to keep looking and finding, and optimising antibiotics.