Two robotic chemical-synthesizing machines tucked away on the fifth floor of the DOE’s Molecular Foundry at Berkeley Lab, are joining the urgent search for new antimicrobial compounds that are effective against constantly emerging drug-resistant bacteria.
Symphony X and Overture, as the machines are named, specialize in creating custom nanoscale structures that mimic nature’s proven designs. And they are fast, assembling dozens of compounds at once.
Peptide-based antimicrobials, despite their potency, can degrade quickly in the bloodstream, limiting their effectiveness. Peptoids, being synthetic, are greatly more durable.
Their durability is one of the reasons why researchers have explored their use as antimicrobials for the past several years.
“Peptoids are modular. We can control every position in their structure chemically and we can create peptoids with very specific traits and functions,” says Ron Zuckermann, director of the Molecular Foundry’s Biological Nanostructures Facility.
“And because we can assemble many similar peptoids at the same time, we can test a hypothesis more thoroughly, in this case focusing on how to create peptoids that mimic antimicrobial peptides,” Zuckermann adds.
Using Symphony X and Overture, Biljana Mojsoska, a graduate student at Roskilde University, created a family of several dozen peptoids, each with a slightly different distribution of charge and water-repelling traits.
Peptoids are composed of non-natural amino acids that are strung together in a chain. The peptoids in this research were about ten amino acids long.
The peptide-based antimicrobialspeptoids, that the new peptoids mimic the structure and function of, have an overall positive charge and water-repelling characteristics, two traits that enable them to disrupt a bacterium’s membrane and kill it.
The problem was assembling a peptoid where these traits are distributed throughout its structure in such a way that the peptoid is most effective at killing harmful bacteria without hurting other cells.
Often, such fine-tuning involves creating compounds one at a time and then testing them, a slow process with many dead-ends. Fortunately, Symphony X and Overture can churn out between 24 and 96 peptoids at a time. This means that many versions can be tested simultaneously.
After assembling the peptoids at the Molecular Foundry, Mojsoska and Prof. Havard Jenssen studied them in their lab in Denmark to determine which versions work best at killing bacteria while not hurting red blood cells. Two promising candidates rose to the top.
“This paper demonstrated the biological compatibility of peptoids compared to antimicrobial peptide analogs,” says Mojsoska. “Through various structural modifications, we were able to tune the structure of tryptophan and lysine-rich peptoids with regards to the hydrophobic content so that we could obtain antimicrobial peptoids with low toxicity profiles.”
Mojsoska B, Zuckermann RN, Jenssen H
Structure-activity relationship study of novel peptoids that mimic the structure of antimicrobial peptides
Antimicrob Agents Chemother. 2015 May 4. pii: AAC.00237-15.
Illustration: Peptoids are chainlike structure of non-natural amino acids that can be assembled to carry out very specific functions, such as fighting harmful microbes. Credit: Annelise Barron