New antibiotics against resistant Gram-negative bacteria make me happy, so I’m very glad to see this report from Genentech. They’ve been doing a lot of work on an antibiotic scaffold (arylomycins, Update: on a program that came in whey they bought RQx) which had not thus far really found much practical use, and it looks like they’ve found what could be a valuable drug.
The arylomycins are natural product antibiotics, but they’re not particularly potent, and have found no use in the clinic. That’s a shame, because their target is of great interest: signal peptidase. Those are key enzymes in an important bacterial signaling pathway, and inhibiting them should lead to all sorts of useful effects. It’s a funny enzyme, though – it uses a catalytic mechanism (serine/lysine dyad) that you don’t see much, and which traditional serine-active-site targeting compounds don’t seem to hit. I should mention that I have personal (unpublished) experience with things that don’t hit signal peptidase I, and I can testify to what a difficult-to-target enzyme class it is.
So any chemical matter that does hit this is worth following up on, but it’s been a hard slog (as it is with all novel antibiotic targets). The Genentech team have put in the work, though, and have extensively modified Arylomycin A while keeping its (essential and funky, for a natural product) biphenyl-peptide-macrolide core, in keeping with clues from the known crystal structures of inhibitor-bound enzyme (see the structures at right). Here’s a writeup at Chemistry World if you don’t have access to the Nature paper, which will give you the main points. The really good news is that the new compounds are potent and efficacious, even against nasty resistant clinical isolates. That’s probably because they’ve never been punched right in the signal peptidase pathway before, and encouragingly, it seems that resistance itself emerges only slowly on repeated exposure.
What comes across as you read the paper, though, is the empirical nature of antibiotic discovery. The peptidase enzyme that G0775 targets is on the inner membrane of the Gram-negative bacteria, so that means you have to get through the outer membrane first. Experiments with defective mutant bacteria indicated that the molecule could actually do that, although you wouldn’t have expected much given its structure. Most antibiotics make it into bacteria through porins, but G0775 apparently manages to bypass that route, and it’s not quite clear how. That alone is definitely worth further study – it’s known that that classic polymixin antibiotics can do this, but G0775 is active (fortunately) against strains with membrane mutations that make them polymyxin-resistant. So there’s something quite interesting going on, and it’s not like we know how to design for it. Also worth noting is that it would seem that G0775 not only makes it in, but manages to not get pumped back out very efficiently either. That’s a common problem with antibiotic lead compounds, and designing away from that is pretty much a black-box process, too.
So the G0775 story represents a great deal of hard work, expertise, and the use of all the tools we have at our disposal in modern drug discovery. But it also has a bit of luck in it. But remember what one of the fathers of bacteriology – Pasteur – had to say about luck in research: “Fortune favors the prepared mind”. And if you’re going to have a successful antibiotic research program, you have to be ready to try a great number of approaches, being as diligent and intelligent as you can, and be ready to run with whatever works. G0775 works, and I hope that its progress in the clinic goes well.