I last wrote about “cryptic natural products” here – this is the idea that there must be a great many interesting compounds produced by microorganisms that we have not seen yet. It’s for sure that there are many biosynthetic-looking gene clusters found in these species that don’t seem to be turned on most of the time, which makes one think that under the right conditions you could perhaps elicit some “break glass in case of emergency” structures that might be well worth seeing.
This was one of the original ideas behind the company Warp Drive Bio (here’s a presentation from 2016 on some of their work), but it’s still not one that everyone buys into. Philosophically, you wonder how many of these pathways are even activatable, and how many are just lost chunks of DNA that are still hanging around. There’s also plenty of debate about how, even if the idea is sound, one goes about getting the organisms to produce their hidden treasures. Here, though, is a new paper from two groups at Princeton that demonstrates the idea in practice.
They’re looking at Streptomyces, a genus that certainly produces some interesting compounds, and seems to have the potential to produce even more. The group used green fluorescent protein (GFP) as a genetic marker, inserting it into some of the “quiet” biosynthetic gene clusters as well as out in more neutral territory, and then ran all sorts of stress experiments on the organisms to see if any of these caused some activity. As it turns out, exposure to etoposide and to avermectin, both quite toxic to the organisms, caused some of these biosynthetic pathways to turn on, and several new compounds emerged, including one with antifungal activity and some that appear to be cysteine protease inhibitors.
What’s more, the group was able to then track down some new information about these pathways, showing that there’s a specific translational repressor protein that keeps them silent under ordinary conditions. That holds out some promise for being able to turn more of these clusters on, and under less drastic conditions. If there are other such repressors scattered around, and if they have any commonality, we could start to get a lot more control over expression of rare natural products. It’s still going to be a lot of work – one of the things that Warp Drive has reported on is that the presence of these gene clusters varies widely among different strains – but there might be a less brute-force way into the field. (I wonder, given that, if the molecules reported in this new paper have already been seen by Warp Drive’s internal efforts or not?)
Like any organic chemist, I admire (and am slightly terrified by) the diversity and complexity of the natural product world. Getting medicinally useful compounds out of it has become progressively more difficult as the years have gone on, in a perfect example of the “low hanging fruit” problem. If there’s a tricky way to cause new active leads to come spilling out of it again, I’m all for it. Not all of them are going to be useful, of course, and not all of them are going to do things that we particularly need done, but some of them may well be good things to have.