Some microbes create powerful drugs and anticancer agents: how? 💊

Scientists from McGill University have discovered how certain microbes create powerful drugs such as antibiotics and cancer treatments.

Their surprising findings could transform the way scientists approach drug discovery and, consequently, pave the way for the production of next-generation drugs, explains Martin Schmeing, lead researcher and professor in the Department of Biochemistry at McGill University and the Centre for Structural Biology Research.


Martin Schmeing and his team studied special proteins known as nonribosomal peptide synthetase enzymes, which act like tiny machines within cells. These "machines" build molecules by linking smaller molecules: amino acids. Despite decades of research, scientists had not managed to understand how these microbes acted to form vital drugs.

To understand this process, the scientists used cutting-edge tools to take detailed 3D pictures of the "machines" at two different times: before and after the binding of amino acids. To achieve this, they had to separate the "machines" to get better "poses" for the pictures, then put them back together.

"Taking 3D pictures of these huge enzymes was like solving a puzzle made of molecules," adds Angelos Pistofidis, lead author and PhD student.

"This study took us years of perseverance and caused many setbacks, but the results were worth it. For the very first time, we have irrefutable evidence of how these enzymes work, and their mechanism turns out to be radically different from what we had imagined until now," says Martin Schmeing.

"Our work demystifies this incredible natural mechanism. We have finally discovered how these microbial machines assemble different elements to form these life-saving compounds. This achievement, which took several decades of work, is the result of a collective effort with our partners at UCLA."

"In fact, microbes are 'engaged in an arms race,' and we have just uncovered the mystery of the crucial step that allows them to manufacture these weapons," explains Martin Schmeing.

He says that originally, scientists thought the process involved basic general catalysis. They now know that the process occurs through electrostatic stabilization within the framework of a concerted reaction.

The next generation of drugs

The discovery could have significant implications for the future of medicine. By analyzing in more detail how these enzymes work, new avenues could be explored for manufacturing next-generation drugs.

"This discovery opens up a world of possibilities," says Martin Schmeing. "These microbial machines already offer us a wealth of treatments. By understanding their mechanisms, we could design them ourselves to create new personalized drugs." The scientists say their study represents a major breakthrough. They could make these machines a reference tool for the discovery of new drugs.

Their findings allow for the creation of a new roadmap for the study of other complex biological systems.

"The innovative methods we developed to study these enzymes could allow us to understand similar molecular machines that are still unknown, which also produce drugs or perform other functions," adds Angelos Pistofidis.

"Fundamental knowledge is important," says Martin Schmeing. "And sometimes, solving the puzzles that nature presents us with opens doors we didn't even know existed."

Martin Schmeing and his team are not done with their research. "Although this study sheds light on the main step in the synthesis of these antibiotics, we still have much to learn from the next 3D pictures of these elegant microbial machines."

The study

The article "Structures and mechanism of condensation in nonribosomal peptide synthesis," by Angelos Pistofidis, Pengchen Ma, Zihao Li, Kim Munro, Ken Houk, Martin Schmeing, and their collaborators at the University of California, Los Angeles (UCLA), was published in Nature. This study was funded by the Canadian Institutes of Health Research and the Fonds de recherche du Québec - Santé.