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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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« Bacteria: Respect Must Be Paid | Main | Roche / Genentech: The Chase Is Over »

March 11, 2009

A Quick Quiz (Re: Antibacterials)

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Posted by Derek

Just as an addendum to this morning's post, a quick question: can anyone name an antibiotic that was brought up through a target-driven approach? That is, not one that's a variation on an existing class, or has its origins in a hey-that-killed-bugs assay. I mean, one that started off with people saying "OK, XYZase looks to be essential in bacteria, and higher organisms don't have it. Nothing's on the market that works that way, but it looks to be a good target, so let's go after it".

Off the top of my head, I can't think of one. There may be an example somewhere, but just the fact that I'm having to rack my brain about it says something. Doesn't it?

Comments (31) + TrackBacks (0) | Category: Infectious Diseases


COMMENTS

1. CMC Guy on March 11, 2009 11:17 AM writes...

Do quinolones meet your criteria? I don't really know their genesis as antibiotics so may be "hey-that-killed-bugs" starting point but know much work in the 80s focused on this class that (if I recall MOA) does target a specific enzyme in bacteria that not in humans.

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2. Derek Lowe on March 11, 2009 11:24 AM writes...

Nope, those go back to an accident, too. Nalidixic acid, the prototype compound of the whole class, was a side product from chloroquine work back in the late 1950s: http://www.baytril.com/6/History.htm

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3. Jose on March 11, 2009 11:41 AM writes...

Recent C&EN story on FTSZ targeted compounds might fit the bill.

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4. Ben on March 11, 2009 11:53 AM writes...

How about the beta lactamase inhibitors?

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5. SciChick on March 11, 2009 12:01 PM writes...

How about isoniazide for M. tuberculosis?

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6. Tim on March 11, 2009 12:06 PM writes...

Avexa has an antibacterial which is currently preclinical but should move into clinical trials in the next 18 months.
Drugs with research codes AVX-13613, AVX-13616, AVX-13617, AVX-13619 and AVX-13781 are all peptides which are designed to bind to both D-Ala-D-Ala and D-Ala-D-Lac growing cell wall terminus.
More info at Thomson Pharma drug id=52682.

Not at market stage yet, but the best example that I can think of.

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7. Ty on March 11, 2009 12:13 PM writes...

I didn't see the C&EN, but a quick survey suggests that FtsZ inhibitors are still in the preclinical stage at best. So are a lot of other "targeted" antibiotics. Guess Derek's question is whether there's any real drug discovered and developed in that way. I cannot think of any, other than those whose target was identified after the fact. I am not in the field, so I cannot be sure.

Another somewhat naive question related to antibiotics is, I've been wondering why so many, if not all, antibiotics have a putative metal chelating motif. Is this just a biased observation or is there any plausible explanation?

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8. Orgmed on March 11, 2009 12:15 PM writes...

Hi Derek,
If not to the market but lots of current work is a target-driven;
1.Targent Therapeutics --Identified a new class of selective RNA polymerase (RNAP) compounds
that exhibit antibacterial properties against S. aureus.
2.Peptide deformylase -- Several companies. 3.MurA/B
4.ZipA
5.As Jose mentioned -- FtsZ -- Wyeth and others
6.Non-b-lactam inhibitors of b-lactamase
7.Linezolide: I am not sure if it is target driven but it targets Ribosome.

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9. Orgmed on March 11, 2009 12:23 PM writes...

My question is if we design target specific MRSA agents, how one can address the plasma protein binding issue. They exhibit very potent activities without serum. When we test them in serum they show no activity. Potent antibacterial agents always have protein binding issues. Any thoughts.

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10. Mad on March 11, 2009 12:26 PM writes...

Not technically an antibiotic but protease inhibitors for HIV fit the design concept.

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11. Derek Lowe on March 11, 2009 12:28 PM writes...

Oh, I know that there's plenty of target-driven stuff going on, and has been for many years. It's just that it's been very hard for any of it to make it all the way to a drug.

As for the specific examples people have brought up: beta-lactamase inhibitors aren't really antibiotics on their own (and the most widely used one, clavulanic acid, is a natural product). FtsZ hasn't made it out of the clinic yet (but good luck to it!) And isoniazid was discovered after nicotinamide was found to have antibacterial effects in the 1940s; the mechanism wasn't clear for many years afterwards.

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12. Tim on March 11, 2009 12:33 PM writes...

What about multi action antibiotics? This paper by Bremner et al ACS Chem Biol, Vol. 1, No. 9. (24 October 2006), pp. 594-600.
describes amplification of berbarine activity by addition of a an efflux inhibitor. More intelligent design that is target orientated.

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13. Yancey Ward on March 11, 2009 12:43 PM writes...

There are a lot of target driven research going on at present, but I can't think of a single marketed drug that arose from such research, but I think the reason is pretty obvious- it was always pretty easy to use the "it kills bugs" approach to anti-bacterial discovery, and, until the last 15 years or so, the historic anti-bacterials were so efficacious that there wasn't much room for new ones.

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14. Lucifer on March 11, 2009 2:12 PM writes...

Ok..

So tell me again.. how were sulfa drugs discovered? By injecting "inactive" dyes in infected rats.

How were organoarsenicals discovered? By following a hunch?

How were the the actinomycete antibiotics discovered? Trial+ error and a system that was willing to spend money on research with poor returns! Most were too toxic for human use- you are just seeing the survivors.

How were the first synthetic anti-malarials discovered? By trying to make crude simplified versions of quinine + a few hunches.

It is not hard, the problem is that MBAs and modern 'drug discoverers' think they can make nature behave and answer questions at their leisure. Hubris!

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15. milkshake on March 11, 2009 2:52 PM writes...

MBAs = Mediocre But Arrogant, and Me Before Anyone. Now, I can think of a perfect shovel-ready project...

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16. CMC Guy on March 11, 2009 2:58 PM writes...

Derek thank you for lesson on quinolone history. I never worked in antibiotics directly (unless making SMs counts) although knew many (lost?) souls that labored in that area. They complained almost as loudly as people doing carbohydrates. As you have done both you must be extra thick skinned to survive.

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17. Lucifer on March 11, 2009 3:01 PM writes...

But guillotines are not shovel ready. It takes some planning to build the infrastructure, collect an angry crowd and organize the event.

"MBAs = Mediocre But Arrogant, and Me Before Anyone. Now, I can think of a perfect shovel-ready project..."

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18. Lynn on March 11, 2009 4:24 PM writes...

Some of the later classes of marketed cell wall antibiotics (monobactams, carbapenems, cephamycin, fosfomycin [all beta-lactams but the last]) were found by screening (natural products)for cell-wall inhibitory phenotypes. Trimethoprim was found by screening pyrimidine derivatives for folate antagonism (antimetabolite activity). But that's it. The parent compounds for all other marketed classes of antibacterials were found by empirical screening. As Derek says, there have been a tremendous number of specific enzyme targeted, using both biochemical and whole cell screens, with many leads generated. Some have reached the clinic - none have made it past Phase I. For various reasons including resistance selection, poor pharmacokinetics, tox, serum binding... The Avexa compounds sound interesting; they are peptides rationally modeled on the mechanism of vancomycin, but designed to hit the van resistant D-ala-D-lac as well as D-ala-D-ala. This is not an enzyme target but a structural target (and unlikely to be subject to rapid resistance selection). Let's see how they do.

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19. Thomas McEntee on March 11, 2009 6:20 PM writes...

So we're spending lots of tax dollars to build telescopes and fund surveys intended to find nasty near-Earth-orbit asteroids that might come close...what are we spending on screening what's here on Earth for new antibiotics? The consequences of an asteroid impact or a steady or increasing rate of evolution of other multi-drug resistant bacteria might be quite similar. As a child I read about Waksman (but it really was Schatz) and the discovery of streptomycin & neomycin. I know, screening's a low-payoff venture but it sounds like the current approaches aren't high ROI ventures either. Can anyone conceive of something, say, microfluidics-like devices, that could be manufactured by the zillions and used to screen the natural products of the planet, including all the dirt, mud, and ooze? Nature's variety is enormous...we have no idea of the numbers of bacterial species. As someone pointed out, these bacteria do battle with one another, pump out defensins and other chemicals. Has anyone thought of high-tech--I'll say Silicon Valley--ways of exploiting what is probably sitting right under our noses?

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20. Bryan Czyzewski on March 11, 2009 6:48 PM writes...

I wanted to point out two things that I hadn't appreciated until recently concerning bactericidal mechanisms: 1) for every natural product used by bacteria in chemical warfare (read: almost all antibiotics ever discovered) there is a resistance mechanism, otherwise the bacteria that produced the substance would not survive; 2) It is better to be bacteriostatic then bactericidal. The former puts less pressure to come up with ways of overcoming the antibiotic.

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21. Bryan Czyzewski on March 11, 2009 6:52 PM writes...

"OK, XYZase looks to be essential in bacteria, and higher organisms don't have it. Nothing's on the market that works that way, but it looks to be a good target, so let's go after it".

Menaquinone inhibitors are a new antibiotic target class that inhibit the alternative vitamin K synthesis pathway that gram negative and some positive use for electron transport.

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22. DR on March 11, 2009 9:46 PM writes...

@17: "But guillotines are not shovel ready."

milkshake may have been inspired by that famous Russian word that covers multiple uses for a shovel.

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23. Lynn on March 11, 2009 11:04 PM writes...

to #19 - it's easy - and relatively cheap - to screen natural product fermentations and extracts for antibacterial activity at quite high throughput - microfluidically, etc. The problem is that the broths and extracts are complex mixtures and identifying novel hits [based on structure] from among the very high number of already-described antibiotics is difficult. So you need "dereplication" systems, which can be via chemical means or biological, or both. In fact, target or pathway-directed screens were originally used as a step in dereplication. You might purify all [easily discernable] components of a broth first [not so easy] and then test for antbiotic activity [this has been tried]- but the general observation is that useful novelty is hard to come by using kill-the-bug-screens against fermentations of standardly isolated organisms. So the key may be to look for generally non-isolated (or previously uncultivatable) organisms. And this is being done. Or use broad whole cell arrays of targeted screens. This should be done [has been attempted but natural product efforts have decreased in big and small pharma]. I do think it's worth doing efficiently on a big scale with serious experienced biology and chemistry support.

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24. Morten G on March 12, 2009 2:13 AM writes...

@ 19 Thomas McEntee

Antibiotic resistant bacteria won't be the end of civilization so it's unfair to compare them to the calamity of an asteroid impact. If they were then how do you explain the existence of civilization before 1940?
And there are a tons of antibacterials right under our noses - that are also toxic to humans, that are photochemically labile, that are almost completely insoluble. So much useless crap in the world.

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25. Resistant on March 12, 2009 9:47 AM writes...

Why do you think this area is low priority for the Pharma's. Can't really do much with it (from a discovery perspective) and, in the end people only buy 2 weeks worth of the stuff anyway.

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26. Hap on March 12, 2009 10:03 AM writes...

There was life before 1940 - just a fair amount less of it (though not as much of it as I thought - about 15 years/person). Much of that is due to antibacterials. The people who are likely to have died of disease and infection are probably more widely spread in age, as well - so you were probably losing more of the productive people than the difference that life expectancy would indicate.

So civilization wouldn't end, but it would probably be less prosperous. And our parts in it would be shorter.

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27. Brooks Moses on March 12, 2009 5:24 PM writes...

Thomas @19: I was reading something a couple of months ago (sadly, I can't recall where) that was reporting on the results of some research into antibiotic-resistant bacteria, and in particular on the encouraging fact that -- as one might hope for -- bacteria tend to quickly lose their resistance to antibiotics when the antibiotics go away. Genetics is nearly always tradeoffs, and when the antibiotic-resistant selection factor is removed, the costs of being antibiotic-resistant mean that the resistance is a hindrance and selected against. And bacteria being bacteria, they adapt quickly and lose it.

The biggest problem is of course in environments like hospitals, where certain antibacterials are pervasive.

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28. srp on March 12, 2009 10:39 PM writes...

Brooks: If you can think of the reference for that article, I'd be interested. I've asked people about this question in the past and never gotten a clear answer.

BTW, I don't see why a small number of doses means that you can't profit from a drug. You should think in terms of price/cure = dose/cure*price/dose. When my flesh is being eaten by some parasite, my sales resistance is also way down.

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29. milkshake on March 12, 2009 11:03 PM writes...

the difficulty is that there are too few patients that are sick enough to be treated with new antibiotics (and hence pay for the development cost). If a new antibiotics turns out to be broadly effective and without natural resistance, it is reserved by the medical community as the drug of last resort (so that the resistance development is held off as long as possible). By the time it becomes widely prescribed it will be off-patent already.

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30. srp on March 13, 2009 8:31 PM writes...

Milkshake:

My thought is that you can charge a super high price for a last-line-of-defense drug because whoever needs it really gets a huge benefit on the margin (of having it versus not having it). So even if they hold it back to the 2% of cases where the other stuff doesn't work you could charge 10-20X as much for it.

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31. Punbutter on March 15, 2009 8:27 PM writes...

Affinium has a compound AFN-1252 in Ph1. This is a FabI inhibitor that I think was actually discovered out of the GSK program.

As for your future posts on the reasons for this difficulty, I recommend reviewing O;SHea dn Moser, . Med. Chem., 2008, 51 (10), pp 2871–2878

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