Monday, September 29, 2014

New Antibiotics = New Targets?

I am about to go to a meeting in Europe where one of the topics of discussion will be where Europe should spend its money on antibiotic discovery research. Of course, geographically – in Europe – sorry Americans.  But what kinds of discovery research should they support with their Euros? I’ve had this conversation so many times now that I am starting to sound like a broken record even to myself.  Every time this topic is raised (with academicians) the first two words out of their mouths are “New” and “Targets.” In theory – this is a great idea.  If the antibiotic hits something entirely new and different than what is hit by existing antibiotics, at least the resistant strains that exist today won’t be resistant (at least mostly) to the new product – until they become resistant that is. And every time I hear these arguments,  I get a little less tactful in my response.  But who cares?  I’m retired – right?  I can say what I want (mostly) – right?

My thoughts run as follows.

Every pharmaceutical company in the world already investigated a very large number of new targets during the 1990s and early 2000s. Just read David Payne’s wonderful exposition of GSK’s efforts in this regard (assuming you have a subscription to Nature or you want to pay). We certainly went through the same trauma at Wyeth and so did Schering and many many others.  Unfortunately, much of the billions of pages of resulting data were never published because the results were, almost 100%, negative! And those of you in the academic world know how hard it is to publish negative data. There were some interesting scientific observations that were published based on this research – but little of the kind of data noted by David Payne and colleagues made it to press. So what will the academic community bring to this table?

First on my wish list would be a way to understand how we can make small molecules enter Gram-negative cells and avoid efflux. This is a basic science research effort that can be separated to a large extent from drug discovery per se. Hans Moser has already published some fascinating work on this topic and additional research is already being funded to some extent by IMI. 

Then, even if we identify a novel target – what makes us think we can find a drug that will work against that target?  Academic researchers in general are not trained to carry out drug discovery research. And when they try to enter the area without adequate training, the results are not good.

So – what do I say to people who ask me if they should spend money on research into novel targets for antibacterial drug discovery in academia?

1.     First – get academics trained in antibiotic discovery research.  They must understand many aspects of translational research that they currently have not even considered. This includes everything from biophysical properties of small molecules to PK/PD to toxicology to chemical manufacturing. This seems like the highest priority to me.
2.     Get people to think about new approaches to existing antibiotic classes.  This is less risky and might well provide more bang for the buck.  How about some additional B-lactamase inhibitors targeting the class D carbapenemases.  Lots of people (Merck and AstraZeneca among others) have worked on this class of inhibitors known fondly as DABCO.  Why not focus efforts on a set of enzymes where there is high medical need?  Are other companies working on this?  Of course.  Have they gotten anywhere? – not to the stage of clinical trials at least according to
3.     Encourage research on known targets using new approaches.  Look at all the binding sites in ribosomes that have not yet been explored.
4.     Finally, if you plan to spend taxpayer money on research in novel antibacterial targets, require researchers to provide a chemically tractable ligand that binds the target and gets into bacterial cells and avoids efflux before you throw too much money at the project. Seed money OK.  Small projects with high risk – OK.  But that’s it.

For more on this topic, my blog contains a number of articles on writing grants for antibiotic discovery (1, 2, 3, 4, 5).  I have also previously discussed the issue of training for academics in antibiotic drug discovery.

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