I’ve had the opportunity to learn more about antibacterial drug discovery in the last year or so – that was one of the few therapeutic areas I hadn’t worked in, actually. And although I already knew that it was no picnic in the park (I’d heard the complaints), doing it myself has given me a new respect for the nasty resilience of bacteria.
I’ve been used to having my compounds go into cell assays, where a good number of them fail. That’s expected – every medicinal chemist knows that some of the potent compounds in the primary assay (against the purified protein target) are going to wipe out when they go up against cells. Cells have membranes, for one thing, and they have bailing pumps built into them to spit out molecules that they don’t recognize. I’ve seen compounds, as has everyone who does drug discovery, that bounce right off the cell assay while closely related analogs work just fine. That’s why you run the assay, to weed those guys out – you may not every understand what specifically went wrong, but you at least get a chance to try to avoid it as you go on.
But bacteria are different beasts. Their independent, free-living nature makes them nastier than even tumor cell lines. Cancer cells, aggressive creatures though they are, still expect to get their food delivered (and their garbage hauled) by the bloodstream. (That’s what makes angiogenesis a drug target in oncology). But bacteria have to search out their own meals, fighting it out with every other bacterium in the area while doing so. Their membranes are like armor plate compared to a lot of higher-organism cell lines, with the gram-negative organisms taking the trophy. Or is it the mycobacteria? (They're both awful, and the proportion of compounds that fail when you move past the pure-protein stage is thus far higher). They react to threats, communicate with each other, and reproduce like crazy. It’s like dealing with a swarm of tiny, self-replicating attack submarines.
So yes, finding an effective new antibacterial drug is a real triumph, and it’s not a triumph that’s been happening very often in recent years. This gets mentioned a lot in the popular press, when they feel like running a Coming of the Superbugs piece, and one of the usual explanations is that drug companies got out of the area years ago because they thought the problem wasn’t big enough to worry about. That’s part of the explanation – or was, quite a while ago. And the finances are different in this space, true. You’re never going to have a multibillion dollar blockbuster, because a new agent is going to be reserved just for infections that are unresponsive to the older drugs. But it’ll still sell.
No, there are plenty of companies working in the area now, and many that never left. And the need for new agents is clear, and has been for quite a while now. The real reason that we don’t have lots of new antibacterial drugs is that it’s really hard to find them, for one thing, and the the bacterial are more than capable of fighting back when we try.
Update: for more on the topic, see here.