Novel antibiotic discovered using computers

It's been dubbed the antibiotic apocalypse. Microbes are becoming progressively more resistant and we're running out of drugs to treat certain infections. At the same time, most of the major pharmaceutical players have exited the antibiotic game because they just can't make enough money. Why? Because if they do come up with a blockbuster drug, then the first thing doctors will do is put it on the shelf and not use it except when they're desperate. Luckily there are still a lot of exciting developments happening at grassroots levels in universities and in startups around the world. And this week, researchers at the Rockefeller university in New York unveiled a new drug that they've discovered that works in an entirely new way to knock out common important bugs that we encounter in the clinic. Sean Brady and his team used computers to trawl through the genetic codes of 10,000 different bacteria from the environment, looking for genes bearing the hallmarks of being the recipe for an antibiotic. Chris Smith found out how they decoded what molecules these genes would make and how they produced them...

Sean - Many of our antibiotics in use today are coming near their end, due to the development of antibiotic resistance. So where do you look for antibiotics? Well, historically, many of our antibiotics have come from bacteria. But what happened is we began to run out of those. The obvious places to go look for new bacteria and interesting antibiotics from bacteria began to run dry maybe 20, 30, 40 years ago. What people have learned over that time period is that maybe we've missed a lot of the antibiotics out there. That hidden within bacteria maybe there are genes, or groups of genes, that might make new antibiotics that would help us revitalize the pipeline for antibiotic discovery.

Chris - One obvious question that springs to mind is, why are microorganisms - bacteria - making antibiotics in the first place?

Sean - That's a good question, right? We don't really know, but a prevailing hypothesis is that they're competing with each other. That they're out in nature competing for limited amounts of food. They can't talk, they can't move very well. And so how do they communicate? How do they keep others away from them? They use antibiotics.

Chris - And I suppose the ones that we focused our attentions on hither to have been the ones that we could spot, we could grow, we could study. And there must therefore be enormous numbers that we've completely missed.

Sean - That's actually what my research group worked on for the past 15 years is this idea that there are many bacteria out in the environment that we haven't been able to bring into the lab because scientists just aren't smart enough to grow them. And so you need to come up with ways in which you could identify the antibiotics they make. One way we worked on this was instead of growing bacteria, we just extracted their DNA, literally extracted DNA from dirt, and then put that into bacteria that do grow. And we've had a tremendous amount of success looking for antibiotics using that strategy. But there's one problem that came up and that was as we clone these genes from the environment, many of them never turn on, which means we can't identify the molecules that those genes should be making.

Chris - Obvious question though, Sean, when you just grab some DNA out of a hunk of soil, how do you know which bits of DNA might be promising candidates for making antibiotic molecules in the first place, so you know to focus your attention on those genes at all?

Sean - Bacteria are smart, but they aren't that smart at the end of the day, and that they've only evolved few dozen ways of making molecules. And that means we can limit our focus to just a small number of gene types. Now they use those gene types to make many, many different molecules, but evolution has only led them down a certain number of pathways. We can quickly filter out lots of the other genes that we know aren't making molecules or antibiotics.

Chris - So you have in your hands, the ability to spot genes that look promising because they've got that sort of hallmark characteristic about them that smells like this could make antibiotics. The problem has been, you can't make the genes turn on. So how have you solved it?

Sean - For a number of years, we've been working on this idea instead of using biology, we would use bioinformatics. So use computer algorithms to look at the genes and predict what they might actually make. Then once we have a predicted structure, we can use synthetic chemistry to actually make that structure. And we identified one that would kill drug-resistant, antibiotic-resistant bacterial pathogens.

Chris - And how good is it as an antibiotic? I mean, before we start talking about whether it'd even work in an animal like us. If you put this on bacteria growing in culture dishes, what sorts of bacteria can it knock out and how good is it?

Sean - It kills a number of pathogens. Staph aureus are one of the famous ones that your audience may have heard of as well as some other bacterial pathogens. And it kills them in a unique way, binds up or takes away building blocks that no antibiotic had taken away before. And it's the new mechanism that is really interesting in addition to just its activity,

Chris - You're saying, in some way, it robs the bacteria of resources so they can't grow properly?

Sean - Exactly. And it does so binding actually two molecules at once. So it's taking two resources at once. Turns out the bacteria, if you just take one resource away, can generally get around that. They eventually develop resistance pretty easily. But if you take away two resources, it presents it an often insurmountable or very difficult to surmount problem. We think that's one of the neat things about this antibiotic and it makes it very difficult for bacteria to circumvent that antibiotic. So no bacterial pathogens that have been found in the clinic that we've tested are resistant to this molecule that we've identified so far. And then when you just test in the lab where you let bacteria grow for long periods of time, they don't develop resistance to this antibiotic.

Chris - In the past, we've found some similarly very exciting potential antibiotics. The problem is when you put them near us, they're awful for us. Have you tested this compound to see if it's tolerable by living things like us?

Sean - So far it's only been tested in mice. We don't see any negative impact. It's not toxic to cells in the lab. And so far in the animal studies we've done, we don't see toxicity to the animals, which is exciting.

Harry - Sean Brady. And he's just published that study in the journal Science.