[Image courtesy of the researchers]
Researchers at MIT are touting a novel method to synthesize a natural compound that has shown potential as an antibiotic.
The chemists produced himastatin using the synthesis method and also managed to generate variants of the molecule, some of which showed antimicrobial activity, according to a news story from the university’s website. The compound appears to kill bacteria by disrupting cell membranes and it gives the researchers hope that they may design other molecules with even stronger antibiotic activity.
In 2016, details were released from the 2014 Review on Antimicrobial Resistance (AMR), commissioned by the UK government to address the concern that superbugs, resistant to current antibiotics, could eventually evolve to the point that the drugs are no longer effective. New Atlas reported at the time that, if such issues aren’t addressed, the AMR found that such superbugs could kill up to 10 million people per year by 2050.
MIT professor of chemistry Mohammad Movassaghi was one of the senior authors of the study, along with MIT professor of chemistry Brad Pentelute. Graduate student Carly Schissel was an author and graduate student Kyan D’Angelo was the lead author of the study, which appeared in Science.
“What we want to do right now is learn the molecular details about how it works, so we can design structural motifs that could better support that mechanism of action,” Movassaghi said in the MIT report. “A lot of our effort right now is to learn more about the physicochemical properties of this molecule and how it interacts with the membrane.”
Himastatin consists of two identical monomer subunits that join together to form a dimer through a bond that connects a six-carbon ring in one monomer to the identical ring in the other, representing a critical aspect of the molecule’s antimicrobial activity, MIT said. The researchers’ approach included building complex monomers from amino acid building blocks through a rapid peptide synthesis technology developed in Pentelute’s lab.
The dimerization method is based on the oxidation of aniline to form carbon radicals in each molecule, allowing researchers to create dimers that contain different types of subunits in addition to naturally occurring himastatin dimers.
“By using solid-phase peptide synthesis, we could fast-forward through many synthetic steps and mix-and-match building blocks easily,” D’Angelo said. “That’s just one of the ways that our collaboration with the Pentelute Lab was very helpful.”
The researchers found that the drug accumulates in the bacterial cell membranes, leading to the notion that it works by disrupting the membrane.
They also designed other himastatin variants by swapping in different atoms in parts of the molecule to test antimicrobial activity against six bacterial strains, finding that some compounds had strong activity but only if they included one naturally occurring monomer along with a different one.
MIT researchers now plan to design more variants that could have more potent antibiotic activity.
“We’ve already identified positions that we can derivatize that could potentially either retain or enhance the activity. What’s really exciting to us is that a significant number of the derivatives that we accessed through this design process retain their antimicrobial activity,” Movassaghi said.
The research was funded by the National Institutes of Health, the Natural Sciences and Engineering Research Council of Canada, and a National Science Foundation graduate research fellowship.