Senior Science Editor
Editor's note: This series highlights recent studies that have used novel approaches to identify antibiotic candidates.
As antibody developers can attest, many antibodies can bind to cells. But most of them don't do anything of therapeutic value after they do.
That same issue applies to the screening of antimicrobial peptides. Binding is comparatively easy to test with current assays, but figuring out whether a bound peptide will be bactericidal is a much longer slog.
Now, researchers have developed a method to quickly screen peptides for bactericidal activities. They engineered the target bacteria themselves to first express peptide sequences as part of a fusion protein and then transport the fusion protein to their cell surface, where it remains connected to the bacterium via a flexible linker sequence. If the peptide has bactericidal activity once it is on the surface, the linker keeps it close enough for it to exert that bactericidal activity.
The team has called its approach, which it reported in Cell earlier this year, Surface Localized Antimicrobial Display, or SLAY for short.
Senior author Bryan Davies, an assistant professor of molecular biosciences at the University of Texas at Austin, told BioWorld MedTech that the approach can be thought of as a sometimes-deadly version of tetherball.
Using SLAY technology, Davies and his colleagues reported on more than 800,000 random peptide sequences in their Cell paper.
Not too surprisingly, more than 98 percent of those peptides had no antimicrobial activity whatsoever.
But even at a hit rate of less than 2 percent, the study identified nearly 8,000 peptides with potential antimicrobial activity in gram-negative bacteria.
More broadly, the research has shown, Davies said, that "there is a much wider range of peptide chemistry with antimicrobial properties than we previously recognized."
"Peptide research has been dominated by what nature gave us, which is predominantly cationic peptides," Davies said. But his team's work has shown that "we are not limited to what nature gave us."
The team plans to follow up on some of the leads it has identified both scientifically – "we now have peptides that have very unique chemistry that have antimicrobial activity, and we have no idea how they work," Davies said – and in terms of their potential as drug leads.
But the SLAY technology itself, he added, is "where I see the real win."
Davies has been working with Avalon Ventures to recently found startup Anexigen Inc. The company will optimize the promising initial leads toward producing clinical candidates and commercialize the platform itself.
The team is refreshingly straightforward in its take on resistance. While explaining why the chances for resistance are low is de rigueur in most antimicrobial discovery efforts, Davies and his co-authors wrote in their Cell paper, "Bacteria have gained resistance to every antibiotic clinically used. There is no doubt they would gain resistance to any antimicrobial peptide discovered."
But if and when such resistance starts to develop, Davies said, the now-resistant bacterium can be subjected to another round of tetherball to find a peptide it is not resistant to.
The SLAY screen, he said, "can be run over and over, and that's the beauty of it."