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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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August 26, 2011

Kibdelomycin, A New Antibiotic. In A Way.

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Posted by Derek

We're going to need new antibiotics. Everyone knows this, and it's not like no one's been trying to do anything about it, either, but. . .we're still going to need more of them than we have. I'm not predicting that we're going to go all the way back to a world where young, healthy people with access to the best medical care die because they decided to play tennis without their socks on, but we're certainly in danger of a much nastier world than we have.

So I'm always interested to hear of new antibiotic discovery programs, and Merck is out with an interesting paper on theirs. They've been digging through the natural products, which have been the fount from which almost all antibiotics have sprung, and they have a new one called kibdelomycin to report. This one was dug out from an organism in a sample from the Central African Republic by a complicated but useful screening protocol, the S. aureus fitness test. This relies on 245 different engineered strains of the bacterium, each with an inducible RNAi pathway to downregulate some essential gene. When you pool these into mixed groups and grow them in the presence of test compounds (or natural product extracts) for 20 generations or so, a check of what strains have moved ahead (and fallen behind) can tell you what pathways you seem to be targeting. A key feature is that you can compare the profile you get with those of known antibiotics, so you don't end up rediscovering something (or discovering something that only duplicates what we already have anyway).
Kibdelomycin.png Now, that's no one's idea of a beautiful structure, although (to be fair) a lot of antibiotics have very weird structures themselves. But it's safe to say that there are some features there that could be trouble in a whole animal, such as that central keto-enol-pyrrolidone ring and the funky unsaturated system next to it. (The dichloropyrrole, though, is interestingly reminiscent of these AstraZeneca gyrase/topoisomerase antibiotic candidates, while both celestramycin and pyoluteorin have a different dichloropyrrole in them).

What kind of activity does kibdelomycin have? Well, this is where my enthusiasm cools off just a bit more. It showed up in screening with a profile similar to the coumarin antibiotics novobiocin and chlorobiocin, and sure enough, it's a topoisomerase II inhibitor. It appears to be active almost entirely on gram-positive organisms. And while there are certainly nasty gram-positive infections that have to be dealt with, I'm more encouraged when I see something that hits gram-negatives as well. They've got more complicated defenses, those guys, and they're harder to kill. It's not easy to get broad-spectrum activity when you're going after gyrase/Topo II, but the fluoroquinolones definitely manage it.

The Merck team makes much out of kibdelomycin being "the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades". And they're right that this is an accomplishment. But the kicker in that sentence is "from natural product sources". Getting gram-positive Topo II inhibitors has actually been one of the areas where synthetic compounds have had the most success. Building off the quinolones themselves has been a reasonably fruitful strategy, and a look through the literature turns up a number of other structural classes with this sort of activity (including some pretty wild ones). Not all of these are going places, but there are certainly a number of possibilities out there.

In short, if kibdelomycin weren't an odd-looking natural product, I wonder how much attention another high-molecular-weight gram-positive-only topoisomerase inhibitor would be getting, especially with only in vitro data behind it. Every little bit helps, and having a new structural class to work from is a worthwhile discovery. But one could still want (and hope) for more.

Comments (14) + TrackBacks (0) | Category: Drug Assays | Infectious Diseases | Natural Products


COMMENTS

1. You're Pfizered on August 26, 2011 11:15 AM writes...

Can you provide a link to the paper? I did a search of the ACS journals and nothing came up...

Permalink to Comment

2. Hap on August 26, 2011 11:53 AM writes...

I don't think you're in luck...

http://www.cell.com/chemistry-biology/abstract/S1074-5521(11)00233-X

Permalink to Comment

3. You're Pfizered on August 26, 2011 12:33 PM writes...

It was my default search. Even SciFinder didn't pull it up. Figured I'd wait for the link, rather than searching everywhere. We get CB here...

Permalink to Comment

4. Hap on August 26, 2011 1:08 PM writes...

No, I was assuming that you didn't have Chemistry and Biology (though the link I found doesn't look like the link Dr. Lowe has - maybe I found the wrong one again?) and hence were not in luck. The link was published nine hours before, so that might explain some of it too.

Permalink to Comment

5. Secondaire on August 26, 2011 4:17 PM writes...

Interesting. The dichloropyrrole also reminds one of pyrrolnitrin and the (much) more recent marinopyrroles.

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6. rubidium on August 26, 2011 5:23 PM writes...

When I was at Big Blue, we were setting out to extract naturally occurring compounds from specimens from the NY Botanical Gardens (Merck cornered the Bolivian Rain Forest), mine coral and other aquatic life for compounds- and of course milk spiders for their venom. There are probably barrels of ether and acetone just waiting somewhere to be put to good use.

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7. DrSnowboard on August 27, 2011 2:52 AM writes...

Do these guys still have jobs? It's getting difficult to distinguish the new discoveries from people clearing their drawers of publishable material. And maybe that's our problem in a nutshell.

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8. Lester Freamon on August 27, 2011 10:33 AM writes...

Didn't Merck kill all natural products research and donate their library?
See (PDF warning)
http://www.ihvr.org/pdf/IHVR_PBJ_Merck_gift_equals_biotech_boost_Reprint.pdf

"Merck exited the natural products drug‐discovery business in 2008 and closed down its 50‐year‐old natural
products research facility in Madrid, Spain"

Permalink to Comment

9. gippgig on August 28, 2011 12:30 AM writes...

This reminds me of the fuss about platensimycin a while back. Novel antibiotics are a dime a dozen - finding something that's medically useful is the problem.
Incidentally, the stereo at C-37 is contradictory.

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10. KCN on August 29, 2011 6:24 AM writes...


Hmm...what? Another novel antibiotics? Where are the troops? Onward march to Kibdelomycin. Hut tu..hut...

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11. simpl on August 29, 2011 6:43 AM writes...

just about on topic - does anyone have any thoughts as to how statins(pl) could reduce infectious deaths?
http://www.theheart.org/article/1269619.do

Permalink to Comment

12. Broth on August 29, 2011 8:38 AM writes...

Statins prevent cytokine storm reaction in flu. Something to remember if swine, bird or h1n1 makes it's way back into the headlines. Forget the flu shot. Put statins in the water supply.

Permalink to Comment

13. barry on August 29, 2011 10:25 AM writes...

the s.aureus screen is ingenious, but of course it tells us nothing about Absorption/Distribution/Metabolism/Excretion i.e. how this structure would fair in a mammalian gut/liver/kidney

the acylpyrollidinedione reminds one of the indandione anticoagulants/rodenticides

Permalink to Comment

14. Anonymous on August 29, 2011 4:08 PM writes...

@12 - You also pick up on the statin-like decalin core of Kibdelomycin? From a biosynthetic point of view this looks like it could be another example of a Diel-Alderase product...

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