This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Researchers from the University of Oxford and international collaborators have revealed previously unseen rapid chemical stages in the formation of β-lactam antibiotics like penicillin, offering insights that can support future antibiotic development. The findings have been published in Nature Catalysis.
Ever since penicillin was developed into a working drug at the University of Oxford in the early 1940s, β-lactam antibiotics have been among the most important medicines for treating bacterial infections. Their activity depends on a special ring—the β-lactam ring—a highly strained chemical ring system that interferes with bacterial cell wall synthesis, ultimately causing the cell wall to fail and the bacteria to die. Scientists have been studying how nature constructs this β-lactam ring for decades, but the key fleeting reaction intermediates have been too difficult to observe directly.
Rising rates of antimicrobial resistance—a process in which bacteria, fungi and other microorganisms evolve to survive the medicines designed to kill them—are undermining the effectiveness of existing antibiotics. With too few new antibiotics in development, understanding how nature builds these molecules is an important step toward replenishing the antibiotic pipeline. In the new study, researchers from the University of Oxford, in collaboration with partners from Diamond Light Source, Lawrence Berkeley National Laboratory, PAL-XFEL and SLAC National Accelerator Laboratory, have used X-ray free-electron lasers to observe the enzyme isopenicillin N synthase, or IPNS, as it converts its linear peptide substrate into the ring system of penicillin.
The new study shows, in unprecedented detail, how the enzyme IPNS achieves an exceptionally complex transformation in a single step. This resolves a long-standing mechanistic question that has remained unanswered for more than four decades. Rather than relying on static X-ray crystallographic structures of the enzyme, the researchers followed the reaction in real time using ultrafast X-ray free-electron laser (XFEL) experiments.
The team captured several rapid stages in the reaction. These include a thioaldehyde intermediate formed just before the β-lactam ring is created and a monocyclic β-lactam intermediate, representing the first ring-shaped structure on the way to forming the complete penicillin scaffold. These steps provide the clearest picture yet of how the IPNS enzyme assembles the penicillin scaffold.
The work also showed that water molecules inside the enzyme play a key role in guiding the reaction. Subtle movements throughout the enzyme help guide these chemical steps, showing that both the enzyme's shape and its chemistry work together to control penicillin formation. To capture the reaction in real time, the researchers used a system in which thousands of tiny droplets containing anaerobic enzyme microcrystals were deposited onto a moving tape 2 mm wide.
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