Asymmetrical Information - Megan McArdle

03.12.13

Worried About Incurable Tuberculosis? Stand By for Incurable Everything.

Antibiotic resistance is a growing problem. Here's why we may not be able to fix it.

As long-time readers know, I'm something of a fanatic on the subject of antibiotic resistance.  My generation is only the second to live its entire lifespan in the age of antibiotic miracles.  My grandparents were born into a world where the son of the President of the United States could die from an infected blister he got while playing tennis without socks.  It was a world where almost everyone over the age of 60 who got pneumonia died (hence it's moniker: "the old man's friend".)  Where surgery was a deadly risk and deaths from childbirth were all too common.  

Most of the lurid abortion statistics that you hear about hundreds or thousands of women dying every year from illegal abortions come from that era too; while the number of deaths was undoubtedly elevated by unsanitary conditions at back-alley abortionists, even abortions in hospitals would have been extraordinarily risky, because the risk of infection could never entirely be eliminated. Most of the decline in deaths from abortions actually came before the Roe decision, and the timing makes it clear that this was mostly due to antibiotics, with a small assist from better blood banking. All of which is to point out that in a world without antibiotics, you'd have to think real hard before undertaking any sort of elective invasive procedure.  

And while we're nowhere near that world yet, we are getting closer.  Totally drug resistant tuberculosis. And gonorrhea, too.  Plus, don't forget the stomach bugs.  So far, these are confined to limited populations, but they seem to be spreading.  

To be sure, we'll never get to the point that Europe reached in the 19th century, where by various estimates, up to 20% of the population died of tuberculosis.  (Thank God for ventilation, and better nutrition.)  But we could definitely get to a point where routine infections would require hospitalization for treatment with highly toxic antibiotics, where the old die quicker and even young lives are more routinely touched by death. Where deafness and infertility and all manner of other impairments are far more common.  In short, the world of childhood storybooks like Little House on the Prairie and Ann of Green Gables.

Part of the problem is the market: antibiotics aren't profitable.  The regulatory hurdles are high, and if you clear them, you get . . . doctors thanking you kindly, and then putting your new product on the shelf as a reserve for when some other antibiotic fails.  By the time they haul it out, the patent may be nearing expiration. A while back, I wrote an article exploring what we might do to fix the market.

Now along comes pharmaceutical researcher Derek Lowe to point out that even if we do fix the market, we might get . . . nothing.  

I realised after my first exposure to antibiotic drug discovery that I’d never had any problem generating cytotoxic compounds against mammalian cells. Happened all the time – not that I wanted it to, of course. But killing bacteria, especially fully armed wild-type bacteria? That was a major event. And even then, most of the compounds you find that can accomplish that will do the same thing to your own cells, which is definitely not the idea.

And that brings up another question about those bacterial targets, the ones that are so orthogonal to human cellular pathways. A disturbing number of them have already been the subject of screening efforts and optimisation attempts – without success. They also seem to be a bit orthogonal to the kinds of structures that medicinal chemists make. There are antibiotics with reasonable-looking structures, but they’re outnumbered by natural-product-derived beasts, complex structures no one would have gotten around to synthetically for another few hundred years otherwise. Perhaps these kinds of things are needed to get in through the bacterial membranes, or needed to avoid being pumped right back out, but it does complicate one’s research.

This all means, it’s sad to say, that the limiting factor in antibiotic drug discovery probably isn’t the amount of money to be made at it. That’s too bad. Money’s a factor that could be adjusted by regulatory agencies, governments, and foundations. But no amount of cash will keep resistant bacteria from being the hard targets they are.

We should still fix the market, of course; the first rule when you're in a hole is to stop digging, and we've been digging ourselves in deeper every year.  But we should also be prepared for the possibility that fixing the market simply won't be enough.  The past hundred years of incredible innovation have conditioned us to the notion that pharmaceutical research is like a vending machine: plug in the right amount of money, and out pops a miracle pill.  And we've definitely been conditioned to the notion that infection is a minor problem, somewhere lower than mosquitoes and broken plumbing, if higher than the annoyance of child safety caps.  We may have to give up on both of those comforting certainties.