Discovery paves way for next-generation medications

As the problem of antibiotic resistance continues to grow, we need new drugs that the bad bacteria in our bodies don’t already know how to avoid. New research by scientists at McGill University represents a major step forward in our ability to develop medicines whose effectiveness will endure in the battle against infections.

The study, published in the prestigious journal Nature, has revealed how molecular machinery inside nature’s microbes builds antibiotics. Researchers have been working on this problem for decades, and this new insight represents a major step forward in our ability to create new drugs and medicines.

Scientists Angelos Pistofidis and Martin Schmeing used the Canadian Light Source (CLS) at the University of Saskatchewan to take groundbreaking pictures of the molecular machinery’s crystal structure.

The molecular machines that Pistofidis and Schmeing studied are called nonribosomal peptide synthetases, or NRPSs. They build some of the most important compounds in current health care and environmental treatments, including antibiotics, anti-cancer agents, and immunosuppressants.

“They have an immense number of applications,” says Pistofidis. “For example, the peptide cyclosporin has been used many, many times as an immunosuppressant for organ transplant operations.”

The breakthrough in their project was capturing images of the NRPS during a key step in the process of building antibiotics. Previously, they had identified the steps involved in NRPS’s production process, but the details were hazy. The synchrotron played a key role in their work.

“The CLS is a world-class establishment. You can very rapidly and very efficiently collect data. It made the whole experience of collecting data on a very complex crystal, like the one that we presented in the paper, quite efficient,” says Schmeing.

Getting the NRPS machine to pause at this step took Pistofidis four years of work, while Schmeing has been working on uncovering the details of this whole process for 15 years.

The work is far from over, as the team wants to gain a deeper understanding of how the NRPSs build larger and more complex structures later in the production line.

“These molecular machines present a clear route to being able to produce new molecules that might help in all sorts of health conditions – whether it is stopping the next viral pandemic, fighting antibiotic resistance or having a big effect against triple negative breast cancer,” says Schmeing.

Schmeing and Pistofidis will be along that route, describing the building blocks for researchers to build these next-gen health solutions.

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Pistofidis, Angelos, Pengen Ma, Zihao Li, Kim Munro, KN Houk, and T. Martin Schmeing. "Structures and mechanism of condensation in nonribosomal peptide synthesis." Nature (2024).

Photos: Canadian Light Source | CMCF Beamline | Researchers

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