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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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May 15, 2014

The Daily Show on Finding New Antibiotics

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Posted by Derek

A reader sent along news of this interview on "The Daily Show" with Martin Blaser of NYU. He has a book out, Missing Microbes, on the overuse of antibiotics and the effects on various microbiomes. And I think he's got a lot of good points - we should only be exerting selection pressure where we have to, not (for example) slapping triclosan on every surface because it somehow makes consumers feel "germ-free". And there are (and always have been) too many antibiotics dispensed for what turn out to be viral infections, for which they will, naturally, do no good at all and probably some harm.

But Dr. Blaser, though an expert on bacteria, does not seem to be an expert on discovering drugs to kill bacteria. I've generated a transcript of part of the interview, starting around the five-minute mark, which went like this:

Stewart: Isn't there some way, that, the antibiotics can be used to kill the strep, but there can be some way of rejuvenating the microbiome that was doing all those other jobs?

Blaser: Well, that's what we need to do. We need to make narrow-spectrum antibiotics. We have broad-spectrum, that attack everything, but we have the science that we could develop narrow-spectrum antibiotics that will just target the one organism - maybe it's strep, maybe it's a different organism - but then we need the diagnostics, so that somebody going to the doctor, they say "You have a virus" "You have a bacteria", if you have a bacteria, which one is it?

Stewart: Now isn't this where the genome-type projects are going? Because finding the genetic makeup of these bacteria, won't that allow us to target these things more specifically?

Blaser Yeah. We have so much genomic information - we can harness that to make better medicine. . .

Stewart: Who would do the thing you're talking about, come up with the targeted - is it drug companies, could it, like, only be done through the CDC, who would do that. . .

Blaser: That's what we need taxes for. That's our tax dollars. Just like when we need taxes to build the road that everybody uses, we need to develop the drugs that our kids and our grandkids are going to use so that these epidemics could be stopped.

Stewart: Let's say, could there be a Manhattan Project, since that's the catch-all for these types of "We're going to put us on the moon" - let's say ten years, is that a realistic goal?

Blaser: I think it is. I think it is. We need both diagnostics, we need narrow-spectrum agents, and we have to change the economic base of how we assess illness in kids and how we treat kids and how we pay doctors. . .

First off, from a drug discovery perspective, a narrow-spectrum antibiotic, one that kills only (say) a particular genus of bacterium, has several big problems: it's even harder to discover than a broader-spectrum agent, its market is much smaller, it's much harder to prescribe usefully, and its lifetime as a drug is shorter. (Other than that, it's fine). The reasons for these are as follows:

Most antibiotic targets are enzyme systems peculiar to bacteria (as compared to eukaryotes like us), but such targets are shared across a lot of bacteria. They tend to be aimed at things like membrane synthesis and integrity (bacterial membranes are rather different than those of animals and plants), or target features of DNA handling that are found in different forms due to bacteria having no nuclei, and so on. Killing bacteria with mechanisms that are also found in human cells is possible, but it's a rough way to go: a drug of that kind would be similar to a classic chemotherapy agent, killing the fast-dividing bacteria (in theory) just before killing the patient.

So finding a Streoptococcus-only drug is a very tall order. You'd have to find some target-based difference between those bacteria and all their close relatives, and I can tell you that we don't know enough about bacterial biochemistry to sort things out quite that well. Stewart brings up genomic efforts, and points to him for it, because that's a completely reasonable suggestion. Unfortunately, it's a reasonable suggestion from about 1996. The first complete bacterial genomes became available in the late 1990s, and have singularly failed to produce any new targeted antibiotics whatsoever. The best reference I can send people to is the GSK "Drugs For Bad Bugs" paper, which shows just what happened (and not just at GSK) to the new frontier of new bacterial targets. Update: see also this excellent overview. A lot of companies tried this, and got nowhere. It did indeed seem possible that sequencing bacteria would give us all sorts of new ways to target them, but that's not how it's worked out in practice. Blaser's interview gives the impression that none of this has happened yet, but believe me, it has.

The market for a narrow-spectrum agent would necessarily be smaller, by design, but the cost of finding it would (as mentioned above) be greater, so the final drug would have to cost a great deal per dose - more than health insurance would want to pay, given the availability of broad-spectrum agents at far lower prices. It could not be prescribed without positively identifying the infectious agent - which adds to the cost of treatment, too. Without faster and more accurate ways to do this (which Blaser rightly notes as something we don't have), the barriers to developing such a drug are even higher.

And the development of resistance would surely take such a drug out of usefulness even faster, since the resistance plasmids would only have to spread between very closely related bacteria, who are swapping genes at great speed. I understand why Blaser (and others) would like to have more targeted agents, so as not to plow up the beneficial microbiome every time a patient is treated, but we'd need a lot of them, and we'd need new ones all the time. This in a world where we can't even seem to discover the standard type of antibiotic.

And not for lack of trying, either. There's a persistent explanation for the state of antibiotic therapy that blames drug companies for supposedly walking away from the field. This has the cause and effect turned around. It's true that some of them have given up working in the area (along with quite a few other areas), but they left because nothing was working. The companies that stayed the course have explored, in great detail and at great expense, the problem that nothing much is working. If there ever was a field of drug discovery where the low-hanging fruit has been picked clean, it is antibiotic research. You have to use binoculars to convince yourself that there's any more fruit up there at all. I wish that weren't so, very much. But it is. Bacteria are hard to kill.

So the talk later on in the interview of spending some tax dollars and getting a bunch of great new antibiotics in ten years is, unfortunately, a happy fantasy. For one thing, getting a single new drug onto the market in only ten years from the starting pistol is very close to impossible, in any therapeutic area. The drug industry would be in much better shape if that weren't so, but here we are. In that section, Jon Stewart actually brings to life one of the reasons I have this blog: he doesn't know where drugs come from, and that's no disgrace, because hardly anyone else knows, either.

Comments (58) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Infectious Diseases


COMMENTS

1. Ben T on May 15, 2014 8:11 AM writes...

What are the chances of getting you on the Daily Show, Derek?

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2. henry's cat on May 15, 2014 8:12 AM writes...

Is it just me, or does anyone else's hackles rise whenever someone (who should know better) says 'a bacteria'? Ugh.

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3. zzlangerhans on May 15, 2014 8:17 AM writes...

Also note the concept that these new antibiotics are supposed to come from the federal government, to be funded by tax dollars. That's a virtual guarantee that any drug to come from the initiative will have no commercial or public health value whatsoever. Blaser seems to be unaware that almost all new drugs come from the private sector and the free markets.

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4. Wifool on May 15, 2014 8:28 AM writes...

Enanta seems to be making an effort:
http://www.enanta.com/research/antibiotics/

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5. lynn on May 15, 2014 8:47 AM writes...

I'm glad you brought this up. I was seething a bit while watching the Daily Show that night. Blaser, indeed knows little about antibiotic discovery. You've laid it out pretty well, Derek [although you've overlooked the two main target areas for antibacterials, cell wall (peptidoglycan)synthesis and protein synthesis]. The GSK paper emphasizes that their chemical libraries were poor [very true]- but even when specific enzyme inhibitors are found, they are hard to turn into good drugs. Can I recommend my own review on why antibacterial discovery is so hard? http://cmr.asm.org/content/24/1/71.abstract

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6. JAB on May 15, 2014 8:47 AM writes...

I have to agree that narrow spectrum antibiotics are a tall order, and that they wouldn't be cheap. Our effort needs to be focused much more on conserving the effectiveness of what we already have in hand. Blazer also seems unaware of how much effort went into microbial genome-driven antibiotic discovery, with no results.

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7. antibi on May 15, 2014 8:48 AM writes...

zzlangerhans - this is so far from being correct but I see it all the time on the comments section on here. Yes the private sector/free market is responsible for the final part of the process. But it would be an unfair assessment to say that most antibiotic agents started there. In fact, many of them started in academia. Somewhere along the line, a company came in a bought the rights to an advanced lead and they take all the credit? No, that's not how it works. In the end, the tax dollars went into the initial work and this model has worked just fine.

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8. Michael Bower on May 15, 2014 8:50 AM writes...

Because the need is still there for new antibiotics, and because the market reasons for leaving the field are so compelling (as illustrated in that GSK article), government-funded antibiotic discovery does seem like one of the only options left. Who else will do it? Hopefully they won't put Blaser in charge of their strategy . . .

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9. Anonymous on May 15, 2014 9:00 AM writes...

A lot of the argument on narrow spectrum development was supported by people with an interest in continued DNA sequencing efforts as they would be the diagnostic gatekeepers. It feeds mostly off the triclosan/efflux pump resistance story where a mechanism of broad resistance develops then spreads from ubiquitous use of an antibiotic.

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10. NMH on May 15, 2014 9:12 AM writes...

I would like nothing better to see over-paid (meaning 100% salary from hard money) academic dead-wood (meaning, they no longer get a grant and are bored to tears) be placed in some kind of government sponsored bacteria/ bacteria resistance learning boot camp and then given sufficient (but not excessive, we are talking potentially lazy academics here) funding to drive antibiotic drug discovery.

But then again, none of my other hypothesis have worked.

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11. Anonymous on May 15, 2014 9:16 AM writes...

"Blaser seems to be unaware that almost all new drugs come from the private sector and the free markets."

To me it seems more that he would like something "new" to be tried, a large scale, governement funded research program. It's not like pharma's overall economic model is very efficient these days.

In addition, +1 to #5, lots of game-changing ideas come from academia. Luckily there are still bright people trying to find new ways to fight bacteria out there.

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12. PJ Hansen on May 15, 2014 9:22 AM writes...

Very good points. I look forward to DL's visit to the show during his book tour.

There has been much discussion of broad-spectrum oral antibiotics killing off helpful bacteria in the gut when prescribed for infections of the lung, skin or where ever. Would switching to more common use of i.v. or i.m. administration be a better approach? Besides the doctor/patient inconvenience and likely sore arm.
A generally knowledgeable friend of mine keeps suggesting this as a prior good practice and I am too young to have experienced it. Is it too impractical for modern medicine?

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13. Hap on May 15, 2014 9:32 AM writes...

Tax dollars fund lots of leads, and interesting ideas (that is why we spend them there, after all), but leads and ideas != drugs. There's still lots of optimization on activity and pharmacokinetics, and then lots of trials, which tend to be the expensive part of finding a drug. In terms of the money and work that goes into finding actual drugs, almost all of it has and probably will come from private companies.

Other than penicillin (maybe), has a drug been put into use where the development (not just discovery) was managed or performed by a government? The absence of experience does not assure that a government can't develop drugs, but it seems unreasonable (and potentially counterproductive, if you implement policy based on on the misconception) to assume that the government already posseses the capacity to develop drugs.

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14. Andrew D on May 15, 2014 9:49 AM writes...

@11 cephlosporins were developed by a UK government development company and licensed to Industry. I expect neorandian propaganda about government research programs on political blogs, not here on an evidence based blog

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15. anon on May 15, 2014 9:49 AM writes...

I'm pretty sure we have narrow spectrum agents, but no one wants the endless compromises of dealing with phages when blister packs of broad spectrum small molecules are getting the job done.
You might have been able to develop a phage drug in 1960's Soviet Russia, but what about 2014 USA?

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16. LittleGreenPills on May 15, 2014 9:51 AM writes...

Hap - I believe Taxol went through a lot of development work at the NCI before being sold to BMS.

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17. Calvin on May 15, 2014 10:01 AM writes...

#5, #12,#14. Let's be realistic. 2 products in 60 years isn't really a good advert for saying that most things come from academia. The reality is that academia can and does do some really useful early stage stuff. But the numhber of groups that can do much past hits-to-leads without serious CRO help is vanishingly small. It's much better than it was but I'd suggest that's because of a substantial influx of people from industry.

Academia does research (and the value here is tremendous don't get me wrong). Academia even dose some translation. But industry discovers drugs >95% of the time. It's that simply.

However, I do think that this field (which is very small) could do with some novel thinking and the best idea might be a better partnership between academia and industry. Who might be willing to fund that?

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18. Hap on May 15, 2014 10:06 AM writes...

From the NCI's article on Taxol, NCI did Phase I trials on Taxol, and mechanism of action studies but they don't note any later trials (when trials get expensive), and the development of methods to get it in quantity had to be done by others.

@12: Did they actually do any trials on the cephalosporins? I wasn't arguing that governments didn't help find potential drugs, but that most of the money and work in drug development is in trials (where most drugs fail), and most of that is spent by businesses.

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19. lynn on May 15, 2014 10:06 AM writes...

#5 antibi - It is true that some of the early antibacterial agents and natural products that were later developed into antibacterial drugs were discovered in academic laboratories, but industry was also very active in natural product discovery in those days. However, one is hard pressed to find academically derived antibacterials since those early efforts that have made it to market. Can you give some examples? I can give some counterexamples: naphthyridines and fluoroquinolones, oxazolidinones, cephamycins, carbapenems, fosfomycin, daptomycin, lipiarmycin [fidaxomicin], chloramphenicol, chlortetracycline, gentamicin, lincomycin, rifamycin, vancomycin, erythromycin...etc. All discovered, optimized and developed by pharma.

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20. Puff the Mutant Dragon on May 15, 2014 10:06 AM writes...

Thanks for this. I saw this interview just the other day and I was kind of blown away by his claim that "we have the science" to make narrow-spectrum antibiotics...it sounded to me like he has no idea how difficult that is. You would need targets specific to certain species or genera of bacteria. Even assuming there ARE such targets and we knew what they are, the market for a drug of this kind would be very limited. I've worked on antibiotic drug development and frankly I find his comments about development of new narrow spectrum agents kind of baffling.

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21. antibi on May 15, 2014 10:13 AM writes...

2? You cannot be serious. There were two name here but there MANY examples and you know it. It's like once people go to industry, they have to become vehemently loyal to the idea that only industry can discover drugs.

SAHA, AZT, cisplatin, alimta, geldanamycin, Byetta, and several biologicals in clinical trials

And add Darunavir (the best HIV-1 protease inhibitor out there) to the list.

http://en.wikipedia.org/wiki/Darunavir

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22. Brett on May 15, 2014 10:14 AM writes...

I'd support more funding for antibiotics research from the government, even if it did just lead us to discover that there's nothing new that works without killing the patient. Mostly because in general I support some subsidies to defray the costs of bringing a drug to market, especially the expensive clinical trials.

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23. leftscienceawhileago on May 15, 2014 10:16 AM writes...

"...rejuvenating the microbiome that was doing all those other jobs..."


Unfortunately we barely have any idea what is in that microbiome, and very little idea what "rejuvenating" means past maybe eating some yogurt after a course of antibiotics....

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24. Barry on May 15, 2014 10:21 AM writes...

In 1773, John Harrison received £8,750 from parliament (albeit not the full "Longitude Prize" of £20,000 [about $4.25million today] that had been offered in 1714) for the chronometer he delivered. Until the advent of GPS in the 1970s, it was descendants of his timepieces that permitted navigators for 200 years to know where they were in the world.
The U.S. embraced a different model, preferring to let the market drive innovation, rather than waiting for our Legislature to post a prize for solving a problem that it deems worthy. For 200yrs, this patent system of granting a period of market exclusivity in exchange for educating your competitors in your innovation has driven a lot of medicine.
But the emergence of antibiotic resistance has revealed the limits of market-driven drug discovery. Twenty years of market exclusivity is a weak incentive to spend the time and money to research and develop a drug that our FDA will reserve for only the direst cases. The drug company will never recuperate its costs that way unless each dose were astronomically expensive. And so we return to the age of government prizes driving innovation at best--or, if our government doesn't act--to a world in which we all risk death from a trivial injury or infection.

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25. Chemjobber on May 15, 2014 10:27 AM writes...

Merrill Goozner* is a big fan of the "NCI was responsible for a lot of drugs before Big Pharma kneecapped them" theory. I don't really buy it, but I don't have the historical knowledge to know if it's true or not.

*Not exactly a fan of pharma, one notes.

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26. Hap on May 15, 2014 10:32 AM writes...

@19: What part of "lead != drug" don't you get, exactly? If you want a drug, even if you know the exact compound, you have to prove that it works; hence lots of expensive trials, where the money comes across. Did the (US) government do any of those trials for those compounds? How many were P2 and P3 (the costs of trials go up exponentially with phase)?

The point of (federally funded) research is to find interesting biology, which leads to potential drugs. Research is really useful; however, there's a big difference between a potential drug and an actual one, though. Getting a compound from killing bacteria in cells or rats to killing them in people (without killing people) is not the same as designing a car and building it; the gap between known and unknown for drugs is much bigger than that for cars, and thus the amount of money and effort that have to be expended to surmount that gap (and the likely failure rate) are correspondingly greater. In almost all cases, the money to surmount that gap has come from companies.

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27. Don B. on May 15, 2014 10:41 AM writes...

In my experience, gram doses of tetracycline are effective against viral pneumonia.

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28. antibi on May 15, 2014 10:46 AM writes...

@ Hap

oh - so what you are saying is that the great contribution of industry is to come in and "optimize" and pay for stuff? Oh well, I cannot argue with you there. But it also makes it sound like industry could be replaced with a banking system?!? This is completely dismissive of how valuable a lead is. But anyway, I'm done arguing here. Keep the blinders on buddy!

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29. JAB on May 15, 2014 10:59 AM writes...

@ChemJobber: my knees are a bit beat up but it was Tonya Harding's thugs done it!

Pharma works with NCI all the time, see the eribulin/Eisai story
Collaborative Innovation in Drug Discovery: Strategies for Public and Private Partnerships
Rathnam Chaguturu
John Wiley & Sons
2014

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30. lynn on May 15, 2014 11:03 AM writes...

#19 antibi
I was speaking of antibacterial agents. You have not named any. Of course there have been academic and government contributions in many parts of drug discovery. Not so much in antibacterials since the days of salvarsan, penicillin, cephalosporin, trimethoprim.

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31. Jose on May 15, 2014 11:37 AM writes...

Re: #11 anon- just a note, using the phrase 'game-changing' in any scientific discourse pretty much negates everything that follows. It's great for MBAs and business dev types, but buzzword bingo doesn't cut it in the scientific trenches.....

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32. Dr. Manhattan on May 15, 2014 11:38 AM writes...

Screening random chemical libraries with lots of "novel targets" has not yielded any new antibacterials. Read Lynn's review (comment 5); it lays out very cogent arguments. Most antibiotics originated in natural products, and most hit a very select subset of essential bacterial physiological processes (peptidoglycan, topoisomerases and ribosomes). Single target compounds quickly engender mutational resistance; the most recent example is the failure, due to resistance development during treatment, of the Anacor/GSK oxaborole compound.

I respect Blaser, but he is mistaken that the science is there to make narrow spectrum compounds.

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33. Kevin on May 15, 2014 11:38 AM writes...

#19 antibi

How many academic labs do you know of that have the following:

GLP assay capability
hERG e-phys setups
Process R&D
Formulation R&D
Packaging and tableting operations
CMC expertise
GMP manufacturing capabilities
Commercialization capabilities
Ability to run GCP clinical trials
Global regulatory expertise
Post-market pharmacovigilance
Competitive market intelligence

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34. Vader on May 15, 2014 11:53 AM writes...

Sigh. So Blaser is the latest victim of Pauling syndrome, in which a person who is brilliant in one field is blinded to his lack of brilliance in other fields.

I've fallen victim to it myself, though I hope I got better. Something for us all to watch out for, in ourselves and our colleagues.

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