Researchers Engineer Enzyme for Enhanced Macrolide Antibiotics

A research team from Tohoku University and RIKEN Center for Sustainable Resource Science has made significant progress in antibiotic development by engineering enzymes involved in the synthesis of the macrolide antibiotic pikromycin. Their findings, published in the journal Chemical Science, provide insights into how modifications to bacterial enzymes can enhance the efficacy of antibiotics.

Macrolides, which include well-known antibiotics such as azithromycin and erythromycin, are critical in treating various infections, including pneumonia and skin conditions. These antibiotics are characterized by a large ring of atoms known as the macrolactone ring, which is essential for their biological activity. However, modifying this structure during the biosynthesis of macrolides has posed challenges for researchers.

Under the leadership of Professor Takayuki Doi from the Graduate School of Pharmaceutical Sciences at Tohoku University and Professor Shunji Takahashi at RIKEN, the team focused on the biosynthesis of pikromycin within the bacterium Streptomyces. Their investigation centered on an enzyme called PikAIII-M5, a key player in this process, particularly its beta-ketoreductase domain.

Engineering Enzymes for Improved Antibiotic Production

The researchers successfully engineered a chimeric version of the PikAIII-M5 enzyme by replacing the beta-ketoreductase domain with a different domain. This innovative approach is likened to swapping parts in a machine, allowing for more precise control over the stereochemistry of the macrolide chains. By modifying these enzymatic components, the team aims to facilitate the creation of new macrolide antibiotics with unique structures not found in nature.

“The application of the chimeric enzyme and synthetic substrate evaluation system established in this research is expected to accelerate combinatorial biosynthesis,” stated Professor Takahashi. This advancement is crucial as the world faces increasing antibiotic resistance and a dwindling pipeline of new antibiotics.

The study’s findings also enable researchers to make more accurate predictions about the chemical structure of naturally occurring macrolide antibiotics based on genomic data analysis. This knowledge can lead to the development of synthetic drug molecules, further expanding the arsenal against resistant infections.

Addressing the Antibiotic Resistance Crisis

As antibiotic resistance becomes an escalating global health threat, the implications of this research are profound. According to Professor Doi, “This approach provides design guidelines for the biosynthesis of novel macrolide antibiotics in the future.” The ability to engineer enzymes effectively could transform how new antibiotics are developed, responding to urgent medical needs.

The research, titled “Characterization of the ketoreductase domain of pikromycin module 2,” is a critical step towards finding solutions to one of modern medicine’s most pressing challenges. As the scientific community seeks to address the growing crisis of antibiotic resistance, the insights gained from this study will play a pivotal role in shaping future antibiotic therapies.

For further details, refer to the study by Tohoku University and RIKEN published in Chemical Science in 2026 (doi: 10.1039/D5SC07470C).