LA JOLLA, CALIF-Self-assembling synthetic peptide “nanotubes” can preferentially punch holes in bacterial membranes. The novel agents may skirt bacterial defenses against conventional antibiotics.

When introduced onto a lipid bilayer, synthesized ring-shaped cyclic D,L-alpha-peptides can self-assemble into micorscopic tubular structures that permit passage of small molecules across the membrane-with deadly effects. M. Reza Ghadiri, PhD, and coworkers recently reported several sequences for cyclic peptides that act preferentially on bacterial rather than mammalian cell membranes, raising the possibility that cyclic D,L-alpha-peptides may be useful in antimicrobial therapy.

In vitro, several cyclic d,l-alpha-peptides effectively killed methicillin-resistant staphylococcus aureus (MRSA) or escherichia coli. Some preferred killing bacteria over mammalian blood cells and even distinguished between particular bacterial species: The minimum MRSA-lethal concentration of one cyclic polypeptide was one twentieth of that required for 50% hemolysis in vitro; another peptide was 13-fold more potent against MRSA than against E coli. The compounds were also effective in vivo: Intraperitoneal injections of 13 mg/kg of one cyclic polypeptide could protect 67% of mice from an otherwise fatal injection with MRSA, and they were apparently well tolerated.

“The [cyclic peptide nanotube] system can self-organize to interact with lipids and polysaccharides on the membrane, so these molecules can ‘sense’ and respond to their environment,” said Dr. Ghadiri, Professor of Chemistry at the Scripps Research Institute in La Jolla, California. “If [cyclic polypeptides] can be stabilized by the membrane, then they form a tube.”

To find peptides that interact more readily with bacterial than with mammalian membranes, the researchers exploited one basic difference: “[B]acterial membranes are more negatively charged, so molecules with positively charged side chains can be adsorbed preferentially,” said Dr. Ghadiri, but this may provide only a 2:1 selectivity. Improving on that specificity required trial and error: To identify selective compounds, the researchers systematically varied peptide sequences and tested their activity in vitro, a process that conceivably might also be applied to discover agents effective against parasites or fungi.

The new agents offer some advantages in the antimicrobial arms race, Dr. Ghadiri said. “Because most [antimicrobial] drugs target specific ligand–receptor interactions, it’s hard to vary their structure much without affecting their antimicrobial action,” he told RESPIRATORY REVIEWS. In contrast, cyclic peptides can be made with a broad variety of sequences. “Nanotubes also have a very fast killing action, so that also reduces the chances that a microbe can become resistant. [Since] the mode is actually permeating the membrane, the bug would have to change its fundamental membrane structure to block this mode of action.”

These barriers to bacterial resistance give Dr. Ghadiri and colleagues hope. “[It] would be my dream come true—that in five to 10 years, there’d be a [new] drug out on the market that could save lives.”

--Mimi Zucker, PhD

Reference
1. Fernandez-Lopez S, Kim H-S, Choi EC, et al. Antibacterial agents based on the cyclic d,l-alpha-peptide architecture. Nature. 2001;412:452-455.