I know that antiviral news is all the thing these days (post coming on that tomorrow), but there’s some encouraging antibacterial news as well, which we could always use. This paper reports progress in the cationic antimicrobial peptide (AMP) area. That’s been a field of interest for a long time, but it’s been tough. Update: here’s a new review of the area. There are a lot of organisms (lower and higher) that produce such agents, but they’re generally (1) not all that stable, particularly in the ways that we would like to administer them, and (2) need pretty high concentrations to be directly antimicrobial. They work by various membrane-disrupting mechanisms, and bacteria (particularly Gram-negative ones) have been seeing that sort of assault for a long, long time now and are accordingly well-prepared.
This latest work (from a large multicenter team headquartered in Singapore) is addressing another strategy, lower amounts of AMPs in synergy with other antibiotics. The idea is that you could affect the bacterial membranes enough to permeabilize them for antibiotic entry, even if you haven’t permeabilized them enough to kill the bacteria outright by just that mechanism. People have tried this before, too, and these attempts have been largely defeated by the other big membrane weapon that bacteria have: efflux pumps. Doesn’t matter that much if your antibiotic wonder drug gets past the membrane if it just gets spewed right back out, and that goes double for Gram-negatives, who have a double-walled membrane structure full of efflux machinery. Forget getting into the cytoplasm; you often can’t even keep your drugs in the periplasmic space between the inner and outer membrane thanks to the pumps kicking in.
But in this case they have an artificial polymer of poly-amidosaccharide and a poly-dimethyl-beta-lactam that gives a cationic species built up of beta-peptide linkages. That makes it more metabolically robust, but the really good part is that this material both seems to permeabilize the bacterial membrane and inhibit efflux. And it has no effect on mammalian cell membranes. In combination, Gram-negative species get killed by antibiotics (such as rifampicin) that normally they aren’t susceptible to (rifampicin being notoriously unable to penetrate most Gram-negatives).
This is shown both in vitro and in vivo, in mouse infection models, and it should be noted that infectious disease is one of the areas with the cleanest translation from small-animal models to human. Mice infected with nasty drug-resistant strains of E. coli, P. aeruginosa, and A. baumannii showed very strong responses to the combination of the polymer and rifampicin, while each agent by itself was completely ineffective. This combination idea even worked with novobiocin, which is almost never any good against most Gram-negatives unless you work up an efflux-crippled strain in the lab. Watching good ol’ novobiocin protect mice against a lethal challenge of A. baumannii (as is shown in this work) is quite something – normally, it would be about as effective in that situation as eating a handful of popcorn.
There are other groups working on similar principles of trying to synergize AMPs and (otherwise ineffective) antibiotics, but this is one of the best I’ve seen. Overall, the idea of using unnatural-ish peptidomimetic species on the AMP side of the combination makes a lot of sense, and I’m glad to see this sort of work delivering some results. We’re going to need them!