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An Anonymous Coward writes:

Dr. Lowe, from In the Pipeline, writes about new discoveries in the field of antibiotics:

Anyone who's done antibiotic research can tell you about what a slog it is. Just looking at the rate of approval of new ones will tell you that, too – it really is like breaking rocks, except breaking rocks is a lot more straightforward and rewarding most of the time. As I've said before, when I look back at all the mammalian cells that I've killed with my molecules over the years, and compare that to the experience I had working against gram-negative bacteria, it's pretty sobering. Killing gram-negative pathogens is hard. And killing them with a compound that (A) hasn't already been discovered, in one form or another and (B) doesn't kill everything else it touches is a challenge indeed.

There are two new papers, though, that give a person some hope. And we need some, because resistant bacteria, as everyone has been saying for years now, could really give our industrial civilization fits. Here's some work by the Hergenrother group at Illinois, though, that sheds light on one of the biggest problems in antibiotic drug discovery: what kinds of structures should we be looking at?

That's a real puzzle, because antibiotic compounds in general tend to have pretty wooly structures, especially the ones derived from natural products. They tend to be outliers in most any rule-of-thumb property screen, and often break several of them simultaneously. Yet they work, and that's impressive, since to "work" in this context means to penetrate a lipopolysaccharide outer membrane, survive on the other side of it without being pumped right back out of the bacterial cell entirely, and penetrate that a second inner membrane in quantities sufficient to serve as a drug.

This paper looks through a set of compounds, carefully measuring the degree to which each accumulate in E. coli, and tried to draw some general structural lessons.

After identifying properties that allow compounds to penetrate Gram-negative bacteria, the research group demonstrates that they can convert an antibiotic that was limited to Gram-positive bacteria to have activity in Gram-negative bacteria.

The second discovery involves greatly improving the potency of a specific antibiotic:

The second paper I referred to is the latest in the series from the Boger group at Scripps, which I last blogged about here. In this latest work (which should, by the time you read this, be here at PNAS) they've been modifying vancomycin, the famous "antibiotic of last resort", which is quite the synthetic challenge (see that link if you haven't looked at its structure; it's a beast). They've managed to introduce variations that improve the potency of the compound substantially (up to 1000x over native vancomycin!), and in this new work they've got a compound that combines greatly improved potency with three separate mechanisms of action. This should make it very hard indeed for bacteria to evolve resistance. That's already a slow process with vancomycin, due to its odd mechanism of action.

Links:
http://blogs.sciencemag.org/pipeline/archives/2017/05/30/antibiotic-progress-and-not-a-moment-too-soon
http://www.nature.com/nature/journal/v545/n7654/full/nature22308.html
https://en.wikipedia.org/wiki/Gram-negative_bacteria
https://en.wikipedia.org/wiki/Gram-positive

http://www.pnas.org/content/early/2017/05/23/1704125114
https://en.wikipedia.org/wiki/Vancomycin

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