Researchers have captured fleeting stages in the reaction that helps build penicillin’s core structure. In a 2026 study, time-resolved X-ray snapshots revealed two previously unanticipated intermediates in the enzyme isopenicillin N synthase (IPNS): a thioaldehyde before β-lactam-ring formation, and a monocyclic β-lactam—the first ring-shaped structure on the route to the complete scaffold.
How does the enzyme make penicillin?
IPNS transforms a linear peptide substrate toward the ring scaffold found in penicillin. The University of Oxford report says the new observations clarify stages in that process that are too fleeting to capture in a conventional static structure.
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The team identified a thioaldehyde intermediate immediately before formation of the β-lactam ring. It also observed a monocyclic β-lactam, the first ring-shaped structure on the route to the complete penicillin scaffold. These are intermediate reaction states, not separate medicines.
The report’s interpretation is that water molecules inside the enzyme help guide the reaction, alongside subtle movements across the enzyme’s structure. The available account does not establish a full atom-by-atom sequence, so the findings are best understood as revealing key stages and features of the reaction rather than every chemical step.
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How researchers assembled the molecular movie
The “movie” is a reconstruction from many timed crystal-structure snapshots, not a video filmed by a camera. The researchers deposited droplets containing anaerobic IPNS microcrystals onto a moving tape 2 mm wide. As the tape passed into an oxygen-filled chamber, oxygen diffused into the crystals and started the reaction.
Changing the tape’s speed changed the delay between the reaction starting and an X-ray free-electron laser (XFEL) pulse hitting the crystals. Each pulse captured a structural snapshot at a different reaction time. By combining thousands of snapshots, the researchers assembled a frame-by-frame account of the reaction. The Oxford report describes the method as capturing short-lived intermediates at atomic resolution under physiological temperature and pressure.
What the discovery does—and does not—mean
Seeing these intermediates gives researchers a clearer mechanistic picture of how IPNS builds penicillin’s core scaffold. That knowledge may eventually help guide enzyme engineering or catalyst design, and could be relevant to future antibiotic development.
This is basic mechanistic research, not a new antibiotic or treatment. The report does not describe a clinical trial, show that existing antibiotics have become more effective, or demonstrate a new way to treat resistant infections.
Independent reader supportYour contribution helps us test, update, and keep practical guides available for everyone.How this work fits with earlier IPNS research
This is not the first molecular movie of IPNS. A 2021 study used complementary X-ray methods to examine correlated motion and oxygen chemistry in the enzyme. The 2026 report adds newly observed intermediates and a more detailed view of the reaction sequence.
The study is listed in Nature Catalysis as “Unanticipated intermediates during isopenicillin N synthase catalysis identified by time-resolved X-ray free-electron laser studies” (2026), DOI 10.1038/s41929-026-01618-4. The University of Oxford’s account is available through Phys.org. The earlier work is described by Berkeley Lab, with a related primary research article available through PubMed Central.
As Christopher Schofield, professor of chemistry at the University of Oxford and a senior author, put it: “Penicillin has shaped modern medicine, but there is still much to learn about how nature builds this important antibiotic structure.”
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