There’s a lot more antibiotic news to cover this week, and I thought I’d start out with some very high-level organic chemistry. This paper from the Myers lab at Harvard is really nice stuff: they’re looking at macrolide antibiotics (such as erythromycin) and trying to find ways to make large number of variations of them from the ground up. Now, that can be a real challenge. I did total synthesis work on a macrolide antibiotic for my own PhD, and it was no stroll through the begonias. Many of these have been made over the years, but there are, to my knowledge, no really practical syntheses.
By “really practical” I mean what a guy like me, twenty-seven years in the drug industry, would mean: synthetic routes that can produce a wide range of structural analogs (to address potency, selectivity, pharmacokinetics, and all the other things that we have to worry about when developing a new drug), while at the same time being reproducible, scalable, and short enough to be industrially feasible. These criteria sort out the existing total syntheses in short order (including, I should most definitely add, my own PhD work). This new paper points out, correctly, that all the commercial erythromycin derivatives are semisynthetic: they start from erythromycin itself, and work what changes can be worked on the existing scaffold. We have organisms that can crank out erythromycin far, far better than any team of chemists can.
Semi-synthesis is a valuable technique, of course. But there’s another thing that you might think of: why not get these organisms to make you a bunch of variations of the original molecule? Well, that’s been tried, too (by researchers at Abbott and others) – the enzymes in the biosynthetic pathway have been dinked and tweaked in various ways, but doing so turns out, in many cases, to be about as hard as doing variations via organic chemistry. You can get molecules this way that no one’s ever had, but they come hard (and nothing commercializable has, to the best of my knowledge, come out of this work with respect to erythromycin).
Some years back, Myers reported a large synthetic effort in the tetracycline area, but this one is even harder. The group has targeted doubly-modified versions of erythromycin: the first change makes them ketolides, a class of compounds where a keto group has been introduced at C-3 (as in telithromycin, cethromycin, and solithromycin). The first of those is on the market, although it has been a wild ride to say the least (see that link for more), and it has significant side effects. The second seems to be safe to use, but has (as far as I know) not demonstrated any particular advantage over existing agents, and the third is in development and seems headed for the community-acquired pneumonia indication. The second modification is expansion of the macrolide ring with an extra nitrogen atom, as in azithromycin, which is well-known as an antibiotic in wide use. There’s really been only one erythromycin derivative reported in the open literature with both of these modifications, and it’s from 1998 and wasn’t particularly impressive.
The Myers group broke this system down into eight intermediates, all of which were prepared on 30 to 150 gram scale. The organic chemistry of these intermediates is very well done, as you’d expect, and as you go through the synthesis, you see the footprints of Woodward, Mukaiyama, and other giants of the field. The macrocyclization, using a technique that Boeckmann developed in the 1980s, is particularly effective, which is a good thing, because closing these large rings is (as we like to say) nontrivial.
So far, that’s how many total syntheses would work, except they’d probably have fewer building blocks (probably just two or three). But that’s by design here – breaking things down into smaller units allows you to make variations without digging way back into the synthetic scheme. For example, the group switches between 14-membered rings and 15-membered rings by making changes in three of the eight subunits. This strategy lets them do what very, very few total synthesis papers are ever able to do:
We prepared an initial library of >300 fully synthetic macrolide (FSM) antibiotic candidates by varying the building blocks in concert with modifying readily diversifiable elements (for example, an azido group, an amino group, a β-keto lactone function, an allyl group) that we introduced into and around the macrolide ring, a powerful tactical combination. In addition to members of the three primary macrocyclic scaffolds discussed in detail above, we prepared a number of other unique scaffolds by modifying the principal coupling components (left- and right-halves) and their modes of coupling using straightforward alternative chemical transformations (see Supplementary Information for a complete list of structures synthesized and Extended Data Figs 1, 2, 3, 4, 5, 6, 7,8, 9, 10 for exemplary schemes for their preparation). This strategy not only provided novel scaffolds to explore, but also permitted deep-seated variations of positions within these scaffolds, thus enabling access to molecules that could not be prepared using semisynthetic methods.
Three hundred analogs! Now that’s the sort of thing you can build a project or two around. And as that quote says, these aren’t just small changes around the edges of the molecules (although you can do, that, too) – they’re variants that are otherwise just completely unobtainable. And also to their great credit, the team went on to screen these in a good-sized panel of bacteria, including (in the later rounds) a number of resistant organisms. They obtained a number of scaffolds with promising activity – none of them are ready to leap into the clinic as is, but they’re definitely of interest. Some of them, in fact, show activity against some rather fiercely resistant strains. Having done some antibiotic drug discovery myself, I can barely imagine a screen of only three hundred compounds that returns a list of actives like this.
There are more to make – the same approach could produce thousands more compounds. It’s still a lot of work, but just getting into the “lot of work” category (and out of the “totally implausible” one) is a big accomplishment. I’m pleased to see the Myers has started a company (Macrolide Pharmaceuticals) to build on this work, and I wish him and his co-workers success.