I’m always happy to hear about new agents to treat gram-negative bacterial infections, especially after a stint working in antibiotic drug discovery myself. Seeing just how hard it is to kill these things did not improve my peace of mind about the problem of bacterial resistance, that’s for sure. So this paper caught my eye, although it’s not exactly a new drug – just a new antibiotic.
Glatiramer acetate (GA) has been a multiple sclerosis drug for many years now – enough years that it’s the subject of a long-running series of brutal patent fights between Teva (who sells it as Copaxone) and competitors, which could be the subject of another blog post all by itself. The drug itself is not a single substance, but rather a mixture of polypeptides containing lysine, alanine, glutamic acid, and tyrosine (constituents of myelin basic protein). It has not-very-well-defined effects on the immune system in MS patients, and seems to reduce the frequency of relapses while not really modifying the underlying progression of the disease itself.
Now it’s been found (by a multicenter team from Denmark, the UK, and the US) that GA is actually a pretty good gram-negative antibacterial agent, with fast bactericidal activity against many species. It’s especially effective against Pseudomonas aeruginosa, and even kills organisms that have formed biofilms. The mechanism looks to be similar to some other antimicrobial peptides, although GA is still active when administered in the context of human plasma (which is the downfall of many other AMPs). That mechanism is almost certainly through membrane disruption, as is the case with other cationic, amphiphilic peptides. The advantage here is that this is a drug whose human safety has already been well-established, because that’s another thing that has tripped up other attempts to use naturally-occurring peptides as systemic drugs.
Some other good news in this area comes from the CARB-X partnership which involves a number of academic and nonprofit research groups. So far, after about a year, they have a good-sized portfolio going:
Of the 17 drug discovery projects CARB-X supported in its first year, 12 focus on ‘traditional’ antibiotics — small-molecule, bacteria-killing drugs.
One-third of these projects are working on drugs with novel chemotypes and new mechanisms of action, offering high development risk but also high reward.
For example, two small molecules inhibit LpxC, the enzyme that catalyses the synthesis of lipid A, a key component of the outer monolayer of Gram-negative bacteria. Another third are advancing new chemotypes for established mechanisms of action, such as new topoisomerase and gyrase inhibitors. The last third act via established chemotypes and on established mechanisms of action, with the lowest scientific and developmental risk but also offering the lowest potential antimicrobial resistance payout.
The new chemotypes against traditional targets are particularly interesting – as that article points out, it’s been a long time since any such molecule hit the market. There are other efforts underway (such as the CO-ADD group) to mine chemical space for insights into penetrating gram-negative bacterial membranes and for new chemotypes in general. Screening in that manner is really a no-brainer; there are so many collections that have never been looked at that we would be completely remiss not to go through them. We’re going to need all the help we can get.