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Biological Chemistry

Prospecting for new antimicrobial molecules in dragon’s blood

ACS meeting news: Small, positively charged peptides from alligators and Komodo dragons could inspire new ways to fight infections

by Michael Torrice
August 22, 2017 | A version of this story appeared in Volume 95, Issue 34

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Credit: Shutterstock
A study of Komodo dragon saliva found 57 strains of bacteria, more than 90% of which were possibly pathogenic. Dracarys!
A photograph of a Komodo dragon walking with its tongue out.
Credit: Shutterstock
A study of Komodo dragon saliva found 57 strains of bacteria, more than 90% of which were possibly pathogenic. Dracarys!

Some reptiles sport tough immune systems that help them fend off infections after suffering gnarly wounds. For example, American alligators can survive losing limbs or chunks of their tails. And Komodo dragons—the largest lizards on the planet—can avoid infections after bites from other dragons, even though the reptiles’ mouths can harbor up to 50 strains of pathogenic bacteria.

At the American Chemical Society national meeting in Washington, D.C., this week, researchers reported a method to discover antimicrobial peptides in the blood of these resilient reptiles. The peptides could inspire novel antibacterial therapies, even against multidrug-resistant pathogens, the researchers said.

This bioprospecting approach in reptiles “is a unique take on natural products isolation chemistry,” said Coran Watanabe, a natural products chemist at Texas A&M University, who was not involved in the work.

All vertebrate animals, not just reptiles, rely on antimicrobial peptides as part of their immune response. These short, positively charged peptides can poke holes in the membranes of pathogenic bacteria, disrupt bacterial gene expression, and turn on other parts of the animal’s immune system to launch an attack on invaders.

Scientists have studied these peptides mostly in mammals, including in humans, other primates, and lab animal species. But Barney M. Bishop and Monique L. van Hoek of George Mason University were drawn to study reptiles’ tough immune systems.

“These creatures have been so successful over millions of years, and we thought that they might have some interesting peptides to study,” van Hoek said.

In a talk in the Division of Biological Chemistry on Monday, Bishop described the method the researchers developed to prospect for antimicrobial peptides in the blood of American alligators (Alligator mississippiensis) and Komodo dragons (Varanus komodoensis).

Previous methods to isolate antimicrobial peptides from blood samples generally involved chromatography or other fractionation methods, which can be time-consuming and can require relatively large samples of blood. Bishop and van Hoek instead rely on custom-made hydrogel microparticles that selectively pick up the peptides.

“By doing this, we can avoid chromatography and work with small sample sizes,” Bishop said. “It’s a short workflow from the sample to the mass spectrometer and can all be done on the benchtop.”

The particles, made from cross-linked poly-N-isopropylacrylamide, contain negatively charged “bait” groups such as acrylic acid or 2-acrylamido-2-methylpropanesulfonic acid, to attract positively charged molecules. The polymer cross-linking helps the particles preferentially capture small peptides and exclude larger proteins.

The scientists incubate these particles in 100-µL samples of plasma and then recover the collected peptides using solvents. They analyze the peptides’ sequences using mass spectrometry.

Using this technique, Bishop and van Hoek’s team have discovered dozens of novel antimicrobial peptides from alligators and Komodo dragons. The scientists used the sequence of one of the dragon peptides to design a synthetic peptide called DRGN-1 that accelerated healing of wounds in mice that were infected with Pseudomonas aeruginosa and Staphylococcus aureus (npj Biofilms and Microbiomes 2017, DOI: 10.1038/s41522-017-0017-2). The team is now investigating ways to incorporate DRGN-1 into possible wound dressings.

Besides wound-healing applications, Bishop and van Hoek are also interested in discovering peptides that could serve as templates for therapies against multidrug-resistant bacteria or bacterial biothreat agents.

The emergence of antibiotic-resistant “superbugs” is a significant public health threat, said Aurijit Sarkar, a pharmaceutical scientist at High Point University. “While it is equally important to identify small molecule antibiotics, [this] work is a beautiful example of human ingenuity that promises potential solutions to the ‘superbug’ problem.”

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