I am a big fan of taking something, either a poster or a talk, to a conference, and getting something back – other than a €6 box of airport chocolates. This blog post is in that spirit.
On the plane to the “Antimicrobial Drug Discovery” conference in Madrid I was reading the Cassandra Project (a novel on smallpox, how apt) instead of the stack overflow of scientific papers I planned to read. Classic JP.
The conference had a mix of experienced, invited speakers and early stage researchers. It was very “biological” for a computational scientist, so quite removed from what I normally do – but an opportunity to learn nonetheless.
The keynote lecture was by Julian Davies, a fantastic speaker who gave a general overview of antibiotics and antibiotic resistance. Antibiotic resistance is a real concern (even those politicians in the G8 noticed a few hours ago!) and there is a fear we might return to pre-antibiotics era when you could not cure common diseases like bacterial pneumonia. Pharmaceutical companies all got out of antibiotic research years ago, and there have been no new antibiotic scaffolds for more than a decade. I found this surprising as you would think that there was a truckload of money to be made from finding the new penicillin. Apparently, there is little return in anti-infectives because of rapid mutation of the pathogen and its short-term use (curing the infection, as opposed to having to take your medication for life, such as beta-blockers for hyperventilation). Bacteria should not only be considered at an individual cell level but also as a population with complex signalling between the individuals (which may offer a way to stop bacterial infection). In order to combat infections and increasing resistance sick patients are now supplied with combinations of drugs – this is still dangerous due to the possible (toxic) drug-drug interactions.
Natural products, e.g. some toxins, are good antibiotics but it is very hard to optimize such compounds to improve their drug profile (chemical synthesis of natural products is difficult). Also a lot of people at the conference were talking of how antimicrobial peptides will save the day. The attendees with drug discovery experience raised an eyebrow about this, knowing how hard it will be to make a 30 residue peptide into a drug.
Some antibiotics work by having a hydrophilic part (e.g. carboxyl) and a hydrophobic part (e.g. an alkane chain). This hydrophobic part sits in the membrane wall disrupting it, which creates a “leak” from the bacteria which eventually kills the pathogen. There are other mechanisms of action such as blocking transporter or signalling channels.
There was a brilliant, energetic talk by Bruno Gonzalez-Zorn with the audience paying rapt attention. He showed how bacteria have these multiple, small plasmids offering antibiotic resistance. He discovered there was a common two-part theme to antibiotic resistance, where a particular gene is always present.
Paul Finn gave a much needed talk on why drug discovery is hard (e.g. target selection, difficulty to get drugs in therapeutic area, potency, toxicity, have to optimize for different variables, etc.). Unknowingly proving this point, there was this earlier talk of a whole optimization series which got a small molecule inhibitor of a viral infection from 150uM down to 1uM (IC50) – a great result in itself, and when the investigators tested this ligand in vivo rather than in vitro it simply did not have any affect on the virus.
Cele Abad Zapatero, one of the main investigators of AltasCBS, made the point that, today, we do not know where we are in drug discovery. He argued we need to move to chemical-biology space instead of simply chemical space and recommended the use of ligand efficiency indices (e.g. BEI, SEI).
And what did I take to the conference? I took a poster, the design of which is based on Dunbar’s stylish template. Marta, Ana and myself won a “highly commendable” poster prize with the best poster going to Laura (Synthetic inhibitors of bacterial cell division targeting the GTP binding site of FtsZ, since you asked). There were 24 posters in all, and mine was the only computational study in a room otherwise filled with phages, bacteria and plasmids (literally as well as metaphorically). There is a sinister heart-warming joy in winning a bottle of wine, instead of a cheque or a certificate. James deserves a sip or two.