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TitleCreation of a macrolide antibiotic against non-tuberculous using late-stage boron-mediated aglycon delivery.
Journal, issue, pagesSci Adv, Vol. 11, Issue 10, Page eadt2352, Year 2025
Publish dateMar 7, 2025
AuthorsYuka Isozaki / Takumi Makikawa / Kosuke Kimura / Daiki Nishihara / Maho Fujino / Yoshikazu Tanaka / Chigusa Hayashi / Yoshimasa Ishizaki / Masayuki Igarashi / Takeshi Yokoyama / Kazunobu Toshima / Daisuke Takahashi /
PubMed AbstractNon-tuberculous mycobacteria (NTM) is gaining clinical recognition as a recently emerging pulmonary pathogen. complex (MAC), the most common NTM, is the cause of pulmonary MAC disease. Currently, ...Non-tuberculous mycobacteria (NTM) is gaining clinical recognition as a recently emerging pulmonary pathogen. 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 to . Screening of to revealed that 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 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 as a promising lead for therapeutics against macrolide-resistant MAC.
External linksSci Adv / PubMed:40043128 / PubMed Central
MethodsEM (single particle)
Resolution2.33 Å
Structure data

61076

9j1m

EMDB-61076, PDB-9j1m:
KU13-bond Mycobacterium tuberculosis 70S ribosome
Method: EM (single particle) / Resolution: 2.33 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

PDB-1l32:
REPLACEMENTS OF PRO86 IN PHAGE T4 LYSOZYME EXTEND AN ALPHA-HELIX BUT DO NOT ALTER PROTEIN STABILITY

Source
  • mycobacterium tuberculosis variant bovis bcg str. pasteur 1173p2 (bacteria)
KeywordsRIBOSOME/ANTIBIOTIC / ribosome / macrolide / ANTIBIOTIC / RIBOSOME-ANTIBIOTIC complex

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