Thursday, 8 January 2015

'Irresistable' antibiotic isolated from caged soil microbe

I often find myself terrified by the development of antimicrobial resistance (resistance to antibiotics, fungicides, etc.) in harmful bugs. I'm terrified as a plant pathologist, because I understand all too well the threat that plant pathogens and pests pose to global food security, and just how reliant we are on biocides to control them. I'm terrified as a pet owner and breeder, observing the staggering frequency with which companion animals present with antibiotic-resistant bacterial infections. And, of course, I'm terrified as a human being, envisaging a future where death due to bacterial infections becomes the norm, rather than the stuff of nightmares, or indeed where infection risks from surgery are deemed too high for currently treatable conditions to be treated.

Sometimes though, I take time out from being terrified to get on with my own research on making plants more resistant to infectious disease (thus reducing the need for antimicrobials in the first place) or to eavesdrop on my colleagues and find out what they're up to. That's how I know that soil is absolutely chock full of unculturable bacteria, which are hard to study in the lab since they just won't grow on a dish or in a test tube. These bacteria are involved in all sorts of processes and ecosystem functions, such as nitrogen and carbon cycling, degradation of agricultural chemicals, and plant growth promotion. As research published yesterday in Nature shows, they might also be an invaluable source of novel antimicrobials.

The researchers in this study were trying to isolate novel antimicrobials from unculturable soil bacteria. The problem, of course, is how to cultivate and study bacteria that won't grow on in the lab. To get around this, the researchers used an Ichip. A what? Quite. In my mind's eye, the Ichip ('I' for isolation) is like a series of tiny cages. A single bacterial cell is captured in each cage, and the Ichip is then placed back in the soil. The gaps between the 'bars' of the cages are too narrow to let bacteria in or out, but big enough to allow fluid and nutrients to move across. It's a bit like the cages divers use around sharks. The diver can't get out and the shark can't get in, but they're both submerged in the same water. This allowed a single 'unculturable' bacterial cell to multiply in each cage - i.e. be cultured.

'Artist's' interpretation of an Ichip

Using Ichips, the researchers managed to culture about 50% of the 'captured' cells, which is a big step up from the 1% that will grow on a petri dish. They did this for 10,000 bacterial cells, and then took extracts from each culture, and tested whether they were any good at killing Staphylococcus aureus - a bug that can cause all sorts of serious infections in humans and animals. Antibiotic resistant strains of S. aureus already pose a major health threat, so finding new ways to kill it are a top priority.
One extract, taken from the culture of a new bacteria called Eleftheria terrae, seemed particularly good at killing S. aureus. The researchers isolated the 'killer' molecule in this extract, which doesn't seem to have been isolated ever before, which meant they got to name it.

They went with teixobactin, which is probably a more modest name than I might have come up with if I discovered a new bug busting molecule. Especially since it wasn't just really good at killing S. aureus, but also a whole load of other disease causing bacteria including Mycobacterium tuberculosis (which causes TB), Clostridium difficile, and Bacillus anthracis. There were other bacterial types that it wasn't so good at killing, but since antibiotic resistant 'staph' and TB are already a major problem it wasn't off to a bad start.

Of course, finding a new class of antibiotic is only part of the battle. The reason why we need new ones is due to the development of resistance to the existing ones. The likelihood of resistance development can be tested in the laboratory by repeatedly exposing a bacterial colony to a sub-lethal dose of an antibiotic, and monitoring whether this alters the minimum dose needed to kill the bacteria. Encouragingly, the researchers didn't find any change in the dose needed to kill S. aureus when doing this, and didn't manage to isolate resistant strains of S. aureus or M. tuberculosis when using lethal doses. The reason for this 'resistance to resistance' is thought to be that teixobactin (I forgot the name of it then, I said I'd have thought of something more snazzy) prevents cell wall formation by binding to the fatty building blocks. Changes in these building blocks, which could create resistance to the teixobactin, are less likely than changes in the protein building blocks, which are targeted by other antibiotics.

However, many promising antimicrobials get this far and then fall down, either because they prove to be toxic to mammals, or because they don't manage to kill bacterial cells inside a living animal. Sometimes because they can't get to the infection site, or because the animal's own cells break down the antimicrobial compound before it can kill the bacterial cells. However, teixobactin jumped all of these hurdles too. At the petri dish stage, it was found to be non-toxic to human cells. Then it was found to be non-toxic to living mice, and persist inside them at bacteria-killing levels for at least 4 hours. It was also completely successful in treating septicaemia (blood poisoning) in mice, after a single dose, and pretty good at treating lung infection too.

So there we have it. A new compound from a mysterious caged microbe, which kills a number of dangerous disease-causing bacteria on plates and in mice and evades resistance by targeting fatty building blocks. Of course, teixobactin hasn't reached its last hurdles. Just because no resistance occurred under laboratory conditions doesn't mean that resistance to teixobactin will never emerge. Also, it has yet to prove safe and effective for human use, but the researchers are optimistic that human trials could start within the next few years. So it might still be one less reason to be quite so terrified.

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