As multi-drug-resistant Gram negative bacteria become an increasingly urgent global threat, the need for effective treatments grows accordingly. Gram negative “superbugs” are particularly nefarious, because their lack of a thick peptidoglycan layer means there’s one less thing for antibiotics to target. But rather than continuing to explore the well-trodden avenues of drug development, our group at the University of Melbourne took a different tack: developing structurally nano-engineered antimicrobial peptide polymers, or SNAPPs – star-shaped nanoparticles used to combat bacterial infections (1). SNAPPs contain peptide sequences based on the standard linear antimicrobial peptides, but their three-dimensional shape allows them to better disrupt the outer membrane of the bacteria. The actual “killing mechanism” is multimodal (including membrane destabilization, unregulated ion movement, and induction of the apoptotic-like death pathway), but it’s initiated when a SNAPP interacts with – and destroys – the integrity of a Gram negative bacterium’s outer membrane.
We had been studying linear antimicrobial peptides for many years, but realized that the 3D structure of the molecules was important. So when chemical engineer Greg Qiao developed a synthesis strategy for preparing star-shaped polymers, we were very keen to test them for antimicrobial activity. So far, we’ve seen great success; our SNAPPs have been shown to have potent (sub-micromolar) efficacy against a range of Gram negative bacteria – including those that are resistant to conventional antibiotics. We’ve even shown that they can protect mice from infection with multi-drug-resistant Acinetobacter baumannii, a bacterium where even colistin (the “last line of defense”) fails. Best of all, and a surprise even to us, was our discovery that the molecules’ toxicity to mouse (or human) cells is relatively low! It’s a promising beginning, but there’s still a lot to be done. At the moment, we’re continuing to improve efficacy by modifying the structure of the SNAPPs, and also working on further reducing toxicity so that our molecules have an acceptable safety margin for human trials. It’s possible that the human immune system might “see” the SNAPPs and develop an immune response to them, although we haven’t seen that happen in our mouse models. It’s also possible that, when used intravenously, the activity of the SNAPPs could be negated by amphipathic molecules in the blood. Those are the types of potential problems we’re attempting to address right now, so I expect that it will be at least another five years before we’re ready for Phase I clinical trials. At that point, though, if we can demonstrate the safety and efficacy of SNAPPs in human patients, they may become the antimicrobial to use when conventional antibiotics fail. Eric Reynolds is a Melbourne Laureate Professor at the University of Melbourne, head of the Melbourne Dental School, and a board member and CEO of the Oral Health CRC, Melbourne, Australia.
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References
- SJ Lam et al., “Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers”, Nat Microbiol, 1, 16162 (2016). PMID: 27617798.
