Since we were just talking yesterday about antibiotics and the misconceptions that people have about them, this is an appropriate time to take a look at an article in the popular press about antibiotic discovery. (Vice.com counts as “popular press”, for sure). The article focuses on the work of Brian Murphy at UI-Chicago, who’s doing marine natural products research, especially on potential antibiotics from marine/freshwater microorganisms. (Update: Prof. Murphy has shown up in the comments to this post, and he wasn’t very happy with the way the article turned out). That’s certainly a reasonable field of research – soil microorganisms have been large tapped out for this sort of work, and the number of marine candidates is surely huge (although difficult to sample and to culture). The article itself is a mixture of accurate reporting and some basic misconceptions:
“It’s a huge gamble,” he said. “We look for unique environments, and we just have to hope that the evolutionary pressures driven by the challenges of trying to survive in these conditions will yield microorganisms which can produce new drug leads. But we have no idea what we’ll find.”
The costs of such ventures, which have taken him across the globe from Thailand to Iceland, can stretch to tens of thousands of dollars. And with this brings pressure. Any organization willing to stump up such money will demand returns on their investment, but nature doesn’t always play ball.
“Such money”? A few tens of thousands of dollars is a roundoff error too small to see in drug R&D. No one’s glaring away, awaiting a return on their thirty-thousand dollar investment in plane tickets and scuba gear. They’re worried about their tens-and-hundreds-of-millions of dollars, the sort of investment that any real compound has to lead to. The article also quotes from William Fenical at Scripps:
Fenical, the professor at Scripps Institute of Oceanography in San Diego, is one of the original marine biomedicine pioneers. He began investigating the ocean’s potential to provide cures for disease in the late 1960s, long before anyone considered it as a science at all.
That’s not accurate, either – Vice’s reporter is laying it on thickly there. Natural product-based drug discovery has been going on for a long time – it was the first sort of drug discovery there was. Marine natural products have been recognized as active drugs ever since antiquity, just like their terrestrial counterparts.
In 2013, Fenical made one of the most interesting antibiotic discoveries in recent years off the coast of San Diego. A bacteria living in the sediment on the Pacific Ocean floor was producing a compound called anthracimycin. Fenical soon found it was capable of attacking the bacteria MRSA, a hospital superbug which is notoriously difficult to treat.
But in many ways, discovering antibiotics is the easy bit. Finding someone interested in investing in developing them is a far greater challenge. Two years have gone by since Fenical identified anthracimycin and no one has shown any interest in taking it from the research lab to the clinic.
That’s worth a closer look. Anthracimycin is an interesting compound, but the article should have mentioned that one of the things that makes it interesting was that it was one of the few natural-product antibiotics discovered in recent decades (although that doesn’t quite fit with the untapped-bounty angle that the rest of the article takes). Cubicin (daptomycin) was discovered in 1986, and hit the market in 2003, and that’s been it for a while. Anthracimycin has what certainly looks like useful activity against various resistant strains of S. aureus,
“We’ve discovered six antibiotics in the recent past,” Fenical said. “Of those, three to four have serious potential as far as we know, including anthracimycin. But we have no way to develop them. There are no companies in the United States that care. They’re happy to sell existing antibiotics, but they’re not interested in researching and developing new ones.”
That line about how there are no companies in the United States that care isn’t accurate, either. It’s true that many of the larger companies have, over the years, pulled out of antibiotic research. But it’s not for lack of “caring”: it’s for lack of ever finding anything. GlaxoSmithKline had a huge investment in new antibiotics, as did AstraZeneca and others. They must certainly were “interested in researching and developing new ones”, and they put their money down and large teams of researchers on it. GSK came up completely empty, after many years of work, and AZ drilled a lot of dry wells, too (although they’ve spun off their anti-infectives research into a separate company).
The usual line is that companies don’t care because they can’t make any money when they do find a new antibiotic, so why bother? But (as just mentioned) there have been large companies pouring money into it, which they don’t do unless they think that they can make it back. Another case in point is Merck’s buyout of Cubist, the developers of daptomycin. They paid over $8 billion dollars to do that deal, which shows that there is indeed money in the field – if you can find something to sell. That’s the hard part, and that’s why companies have been pulling out.
This article is conflating an apparent lack of interest in developing anthracimycin (so far) with the difficulties in developing any new antibiotics at all. So why isn’t anthracimycin going forward? One reason may be that the compound has no activity against gram-negative bacteria, which is one of the biggest unmet needs in the field. A chlorinated version, which makes it similar to a known soil-organism natural product, chlorotonil A, gives it some gram-negative activity, but not much. Another tricky part is patent coverage and IP. There’s an earlier Japanese patent application (PCT/JP 2011/010586) that appears to have the compound in it, for example. And another problem is availability. A five-liter fermentation of the marine organism gave about 6 milligrams of anthracimycin, which means that getting enough to work with is going to take a significant investment. To turn this into a drug, you’re going to need enough to scoop it around like flour out of a bag.
Back to the Vice article:
Fenical’s frustrations stem from the fact that developing new antibiotics is in some ways far easier than developing treatments for other diseases such as cancer.
The main way in which it’s easier – and it’s a big one – is that the assays and animal models are far more predictive. But having lots of good means to develop a compound does not help you when you can’t find much chemical matter to develop, or many good targets to develop anything against, and there cancer (and many other therapeutic areas) have raced ahead. The huge majority of existing antibiotics work through a very short list of mechanisms, as opposed to (say) cancer, where there are a wide variety of targets that have been prosecuted at all stages of the disease (with more in the works). When you do big natural-product screens for new antibiotics, then, you mostly find nothing, and what you do find is almost always something that was already known, or works against a target that’s already known. I’d say the biggest interest with anthracimycin is in figuring out how it works – does it hit something that we already hit? Or if it has a new mechanism, then the thing to do would be to work up some targeted screens and see what else you can find.
The article mentions another natural product discovery by Fenical and his group, diazonamide A, and that’s worth looking at in light of just those issues. The compound showed promising anticancer activity, but was extremely difficult to isolate in any quantity from its natural sources. That led to a lot of total synthetic work (there have been several total syntheses thus far, but needless to say, none of them can provide the compound in development-level quantities). Work on the compound’s mechanism of action, though, showed that it has an interesting microtubule effect (probably through ornithine delta-amino transferase), and this mechanism is being studied further as an oncology target. A small company has been formed to try to develop a simpler version of the diazonamide structure itself as a new oncology agent as well, which is something you won’t get from the Vice writeup, either.
Producing antibiotics, on the other hand, is far less environmentally invasive. All scientists need is to collect a few cells of the antibiotic-producing bacterium, which can then be cultivated en masse, enabling the production of the chemical on an industrial scale.
Unfortunately, that’s the sort of thing you will get from the Vice article. And as anthracimycin itself demonstrates, that’s not always how it works. When you find an active natural product, sometimes you can’t even identify the organism that’s making it. And many of those can’t be cultured in the lab. Even when you do, the bacterium or fungus responsible might not make very much of it under lab conditions, or it might not make very much of it under any conditions at all, no matter what. This is not the trivial problem that the above quote suggests.
The article does make some good points, and it does get some things right. But what it leaves out and what it gets wrong make it hard for a lay reader to figure out what’s really going on in antibiotics, and with natural product drug discovery in general.