McGill University researchers have discovered how certain microbes create potent drugs like antibiotics and anti-cancer therapies.
Their surprising findings could change the way scientists approach drug discovery and pave the way to the designing of next-generation medications, explained Martin Schmeing, principal investigator and professor in McGill's Department of Biochemistry and Centre for Structural Biology.
Image by Claire Loewen/McGill University.
Schmeing and his team studied special proteins called nonribosomal peptide synthetases, which act like tiny machines in cells. These "machines" build molecules by connecting smaller pieces called amino acids. For decades, exactly how these microbes worked to form life-saving medicines eluded scientists.
To understand the process, the researchers used advanced tools to take highly detailed, 3D pictures of the "machines" both before and after they connected the amino acids. To do this, they had to split the "machines" in a way that provided the best "poses" for pictures, and then put them back together.
"Taking 3D pictures of these massive enzymes was like solving a molecular jigsaw puzzle," added Angelos Pistofidis, lead author and PhD student.
"It took years of persistence and many setbacks, but the results were worth it. For the first time, we have a smoking-gun view of how these enzymes work, and it's not how anyone guessed," Schmeing said.
"Our work helps demystify this incredible natural process. We've finally unveiled how these microbial machines piece together building blocks to form these lifesaving compounds. It's an achievement decades in the making, and was a great team effort with our UCLA collaborators".
The microbes are in effect "engaged in an evolutionary arms race with one another," explained Schmeing, "and we now understand the most important step in how they make these weapons."
He said scientists traditionally thought that the process involved general base catalysis, but now understand that it's through electrostatic stabilization in a concerted reaction pathway.
Designing next-generation drugs
The discovery could have wide-reaching implications for medicine. A detailed understanding of how these enzymes operate stands to unlock new pathways for designing next-generation drugs.
"The potential is enormous," Schmeing said. "These microbial machines are already a treasure trove of therapeutics. Understanding their mechanisms could allow us to engineer them for new, custom-designed drugs." The findings represent an important step forward toward making these machines a go-to tool for drug discovery, the researchers said.
This finding also establishes a new roadmap for studying other complex biological systems.
"The innovative methods we developed to study these enzymes could pave the way for understanding similarly elusive molecular machines, whether they make medicines, or have a different job," added Pistofidis.
"Fundamental knowledge is important," Schmeing said. "And sometimes, solving the puzzle of nature opens doors we didn't even know existed."
Schmeing and his team aren't finished with this research. "Although this study illuminates the central step in synthesis of these antibiotics, we have lots more to learn from the next 3D pictures of these elegant microbial machines."
About the study
Structures and mechanism of condensation in nonribosomal peptide synthesis by Angelos Pistofidis, Pengchen Ma, Zihao Li, Kim Munro, Ken Houk, Martin Schmeing, and their UCLA collaborators was published in Nature. It was funded by the Canadian Institutes of Health Research and Fonds de recherche du Québec - Santé.
