There's an idea that shows up in the antibiotic field that seems a bit crazy by the standards of other therapeutic areas. Since bacteria develop resistance to single agents, why not take two different classes of antibiotic molecule and, y'know, string 'em together somehow? How about that, eh?
Well, it's the sort of thought that occurs either to people who don't know much about drug discovery, or to those who know an awful lot. In between, you're probably going to dismiss that one as something of an eye-roller. But while it's got some problems, it's not quite as much of a bozo move as it appears. Here's an example that just showed up in J. Med. Chem., where a group tied Cipro (ciprofloxacin) to neomycin.
The first objection is "Why don't you just give people two pills, instead of trying to make them all into one molecule?" (Here's a review that talks about both options). Well, one answer is that two different agents are going to have different absorption and PK, whereas a conjugate drug will be coming on all at the same time, which could be an advantage. But a more compelling answer is that the new conjugate is going to be a different creature at both of its drug targets, and might well be different enough at both to qualify as a new agent to the resistant strains.
The molecules described in that paper above are, depending on your point of view, fluoroquinolones with a lot of sugars hanging off of them - most unusual as far as traditional quinolone SAR - or neomycin oligosaccharides with some odd heterocycles hanging off of them in turn, which is also not the sort of thing that's usually tried on that scaffold. So if you can still hit both targets, you may well be able to hit them with something they haven't seen before (and may not yet know how to deal with). Importantly, in the case of those quinolone/neomycin thingies, some evidence is shown in the paper that bacteria have a harder time developing resistance to the new compounds. (In order to completely evade them, the bacteria will have to mutate out of both targets, too, but that advantage mostly holds with two separate pills as well).
But all this brings up the second objection: how do you think you're going to get away with hanging all that stuff off an active compound? Well, that's why this trick is usually done with known antibiotics. The SAR of these things has been well worked out by now, and that includes the parts of the molecule that don't seem to have much effect on things. Those will be the preferred positions to attach your linking groups, they're the nonessential region(s) of the molecule that can be messed with.
There's a potential show-stopper in all this, though, and it can be seen on display in the J. Med. Chem. paper. Sticking two drug molecules together, no matter how you do it, is going to make a rather large entity. Neomycin, for its part, didn't start out very small, and the linkers used in this paper aren't the tiniest things on the shelf, either (although I do like the use of the triazole click reaction, mentioned yesterday as well). It turns out that the resulting double-barreled compounds are better than plain neomycin, but worse than plain Cipro. And this happens in spite of the fact that when you assay them against the fluorquinolone target enzymes (DNA gyrase and topoisomerase IV), the new compounds are actually more potent than the original drug. So what's the problem?
Well, the problem, almost certainly, is that these things are probably just too huge. The disconnect between enzyme and bacterial potency here may well reflect trouble getting into the bacteria (although that doesn't seem to be hurting the neomycin end of the activity so much). Larger molecules are trouble when dosed orally, too, and I'd expect compounds like the ones shown to be difficult to develop as traditional pills. (That said, there's a real need for IV-based antibiotics for nasty hospital-derived infections, so something like this could still fly, as long as it showed activity against real bacteria).
So this idea is hard to realize, but it's not necessarily crazy. It keeps showing up in the antibiotic world, and here's an account of the same concept being applied to malaria therapy. Eventually someone's going to get this to work.