A new angle of attack

MELBOURNE, Australia--A team from the University of Melbourne recently published a study on a new treatment method for antibiotic-resistant bacteria—and the interesting part is that it's not a new class of antibiotics.

The approach in question involves tiny star-shaped molecules comprised of short chains of proteins known as peptide polymers, which were created by scientists from the Melbourne School of Engineering. The team for this effort consisted of members of several departments, including Prof. Greg Qiao and PhD candidate Shu Lam, from the Department of Chemical and Biomolecular Engineering, as well as Associate Professor Neil O’Brien-Simpson and Prof. Eric Reynolds from the Faculty of Medicine, Dentistry and Health Sciences and Bio21 Institute.

The results were published in Nature Microbiology in a paper titled “Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers.”

Qiao and his team have been working with peptide polymers for several years, and recently, created this star-shaped type, which was found to be highly effective at killing Gram-negative bacteria, yet non-toxic—to the point that the dosage rate would need to be increased by a factor of more than 100 to be toxic.

The SNAPPs are capable of killing bacteria with multiple pathways, while most antibiotics rely on a single pathway. One such pathway is simply ripping apart the cell wall of bacteria, which causes the cells to trigger apoptosis and destroy themselves.

The safety of these polymers is due to their size, as they are too large to enter healthy cells. Qiao commented to Marcus Strom of the Syndey Morning Herald that “With this polymerized peptide, we are talking the difference in scale between a mouse and an elephant. The large peptide molecules can't enter the [healthy] cells.”

The star-shaped polymers are known as “structurally nanoengineered antimicrobial peptide polymers” (SNAPPs), and as noted in the paper, “exhibit sub-μM activity against all Gram-negative bacteria tested, including ESKAPE and colistin-resistant and MDR (CMDR) pathogens, while demonstrating low toxicity. SNAPPs are highly effective in combating CMDR Acinetobacter baumannii infections in vivo, the first example of a synthetic antimicrobial polymer with CMDR Gram-negative pathogen efficacy.”

The SNAPPs were tested against six kinds of drug-resistant bacteria, with no signs of resistance, even in later generations. More work needs to be done, however, as only one type was tested in animal models. Still, the results so far are more than encouraging.

“We did not observe any resistance acquisition by A. baumannii (including the CMDR strain) to SNAPPs. Comprehensive analyses using a range of microscopy and (bio)assay techniques revealed that the antimicrobial activity of SNAPPs proceeds via a multimodal mechanism of bacterial cell death by outer membrane destabilization, unregulated ion movement across the cytoplasmic membrane and induction of the apoptotic-like death pathway, possibly accounting for why we did not observe resistance to SNAPPs in CMDR bacteria. Overall, SNAPPs show great promise as low-cost and effective antimicrobial agents and may represent a weapon in combating the growing threat of MDR Gram-negative bacteria,” the authors reported in their work.

Antibiotic-resistant bacteria, which have mutated to develop defenses against antibiotics, are one of the top health threats worldwide.

“It is estimated that the rise of superbugs will cause up to ten million deaths a year by 2050,” said Qiao. “In addition, there have only been one or two new antibiotics developed in the last 30 years.”