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March 13, 2009
Drugs For Bacteria: Really That Hard, Or Not?
A few readers have told me that I’m being too hard on antibacterial drug discovery, at least on target-based efforts in the field. The other day I asked if anyone could name a single antibacterial drug on the market that had been developed from a target, rather than by screening or modification of existing drugs and natural products, and the consensus was that there’s nothing to point to yet.
The objections are that antibacterials are an old field, and that for many years these natural products (and variations thereof) were pretty much all that anyone needed. Even when target-based drug discovery got going in earnest (gathering momentum from the 1970s through the 1980s), the antibacterial field was in general thought to be pretty well taken care of, so correspondingly less effort was put into it. Even now, there’s still a lot of potential in modifying older compounds to evade resistance, which is not something that a lot of other drug discovery areas have the option of doing.
And I have to say, these points have something to them. It’s true that antibacterials are something of a world apart; this was the first field of modern pharmaceutical discovery, and the struggle against living, adapting organisms makes it different than most other therapeutic areas even today. The lack of target-driven successes is surely due in part to historical factors. (The relative success of the later-blooming antiviral therapeutic targets is evidence in favor of this, too).
That said, I think that it’s not generally realized how few target-based drugs there are in the field (approximately none), so I did want to highlight that. And it does seem to be the case that working up from targets in the area is a hard row to hoe. There’s a rather disturbing review from GlaxoSmithKline that makes that case:
"From the 70 HTS campaigns run between 1995–2001 (67 target based, 3 whole cell), only 5 leads were delivered, so that, on average, it took 14 HTS runs to discover one lead. Based on GSK screening metrics, the success rate from antibacterial HTS was four- to five-fold lower than for targets from other therapeutic areas at this time. To be sure, this was a disappointing and financially unsustainable outcome, especially in view of the length of time devoted to this experiment and considering that costs per HTS campaign were around US$1 million. Furthermore, multiple high-quality leads are needed given the attrition involved in the lead optimization and clinical development processes required to create a novel antibiotic.
GSK was not the only company that had difficulty finding antibacterial leads from HTS. A review of the literature between 1996 and 2004 shows that >125 antibacterial screens on 60 different antibacterial targets were run by 34 different companies25. That none of these screens resulted in credible development candidates is clear from the lack of novel mechanism molecules in the industrial antibacterial pipeline. We are only aware of two compounds targeting a novel antibacterial enzyme (PDF) that have actually progressed as far as Phase I clinical trials, and technically speaking PDF was identified as an antibacterial target well before the genome era."
So although the history is a mitigating factor, the field does seem to have its. . .special character. The GSK authors discuss some of the possible reasons for this, but those can be the topic of another post or two; they're worth it.
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