Wednesday, December 15, 2010

Searching for antibacterials under the lamppost

We all know that we need more antibiotics and the ones we have are no good. We all also know that bugs become more and more skilled in avoiding being killed, and this is no good either.

The question here is why don't we have new antibiotics coming. And it turns out to be real hard to make one. Initially we had a discovered a whole bunch of these from natural components. All these were developed by bacteria and fungi to kill other bacteria and fungi, and these chaps had billions of years to develop these components. We just hijacked their research, really.

When all these started to age because of the pathogens rapidly acquiring resistance, big pharma decided to have a go at making new antibacterials. Hey, we are pretty good at fighting cancer, killing some bugs should be a walkover.

Here is a great example how we fail. By "we" I mean GlaxoSmithKline, who are no amateurs. They constructed a library of constructs, which would produce genes of interest at different expression level - and that would be all the genes in the genome they could clone that way!,  and tested all these against all the compounds they had on their shelves. ...WOW!

Many, many monies later: 10 hits, no leads, no drugs. Game over.

But let us imagine that there would be drugs developed. What next? These would be the last line of defense, and will be proscribed very, very rarely. This creates a problem of profit in the antibiotics R and D: even if you develop a new antibacterial, there will be no money coming you way.

Well then, pharma can not help us... How about academia?

There is some hope there. A couple of new approaches has emerged.  One is grafting one antibiotic scaffold on another, creating a hybrid werwolf antibiotic, which kills like hell. However, majority of the academia peoples just figured out that anything is an antibiotic target, and that anything is an antibiotic, and they started killing their favorite proteins or RNA in vitro. And yes, if you inhibit something important, your bug will die.

RelA is no exception. Several ppGpp analogues were developed as lovely antibacterials: exhibit 1 and  2. (A quick reminder - RelA makes ppGpp from one ATP and one GDP molecule, and ppGpp in turn acts as a molecular messenger remodeling the whole bacterial physiology, thus RelA is very important for bacterial virulence - a great target for an antibacterial indeed!).

Does it look promising? Not at all. It is not enough to inhibit something important. You also need to be specific and you also need to get into the cell. The latter is a very, very big problem - you need to follow the Lipinski's rule of five, and ppGpp is a very, very bad scaffold to start with in this case: loads of hydrogen bond donors, loads of acceptors, too big and not hydrophobic enough.  All bad. Well, the only things that are good is grants acquired and papers published.

So here we are. Big pharma bails out, academia has no idea as to what they are doing. Any chances of our survival?

Yes. Small start-up pharma packed with academia-derived know-how. Rib-X, Tetraphase. Pray for them, please.


Payne DJ, Gwynn MN, Holmes DJ, & Pompliano DL (2007). Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature reviews. Drug discovery, 6 (1), 29-40 PMID: 17159923

Charest MG, Lerner CD, Brubaker JD, Siegel DR, & Myers AG (2005). A convergent enantioselective route to structurally diverse 6-deoxytetracycline antibiotics. Science (New York, N.Y.), 308 (5720), 395-8 PMID: 15831754

Mendeley group on stringent response

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