| Author |
Isozaki Y, Makikawa T, Kimura K, Nishihara D, Fujino M, Tanaka Y, Hayashi C, Ishizaki Y, Igarashi M, Yokoyama T, Toshima K, Takahashi D.
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| 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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