2. Academic Validation
  3. Creation of a macrolide antibiotic against non-tuberculous Mycobacterium using late-stage boron-mediated aglycon delivery

Creation of a macrolide antibiotic against non-tuberculous Mycobacterium using late-stage boron-mediated aglycon delivery

  • Sci Adv. 2025 Mar 7;11(10):eadt2352. doi: 10.1126/sciadv.adt2352.
Yuka Isozaki 1,  Takumi Makikawa 1,  Kosuke Kimura 1,  Daiki Nishihara 2,  Maho Fujino 2,  Yoshikazu Tanaka 2 3,  Chigusa Hayashi 4,  Yoshimasa Ishizaki 4,  Masayuki Igarashi 4,  Takeshi Yokoyama 2 3,  Kazunobu Toshima 1,  Daisuke Takahashi 1
Affiliations

Affiliations

  • 1 Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
  • 2 Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan.
  • 3 The Advanced Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan.
  • 4 Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
PMID: 40043128 DOI: 10.1126/sciadv.adt2352
Abstract

Non-tuberculous mycobacteria (NTM) is gaining clinical recognition as a recently emerging pulmonary pathogen. Mycobacterium avium complex (MAC), the most common NTM, is the cause of pulmonary MAC disease. Currently, the Macrolide azithromycin (AZM) is the standard first-line Antibiotic for treatment of the disease. However, the rise of drug-resistant MAC necessitates the development of alternative therapeutics. Here, we present a late-stage boron-mediated aglycon delivery strategy for selective modification of AZM, generating a library of potential anti-MAC drugs designated KU01 to KU13. Screening of KU01 to KU13 revealed that KU13 exhibited enhanced antimicrobial activity against wild-type and macrolide-resistant MAC compared to AZM. Cryo-electron microscopy analysis indicated that the inserted tercyclic moiety of KU13 formed a robust anchor on the Bacterial ribosome, creating a binding pocket with base flipping of U2847, potentially bypassing the standard mechanism of Macrolide resistance. These results position KU13 as a promising lead for therapeutics against macrolide-resistant MAC.

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