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Issue 12, 2014
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Synthesis, broad spectrum antibacterial activity, and X-ray co-crystal structure of the decoding bacterial ribosomal A-site with 4′-deoxy-4′-fluoro neomycin analogs

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Abstract

This study reports the synthesis, antibacterial evaluation and nature of fluorine–rRNA contacts revealed by an X-ray co-crystal structure of a series of 4′-deoxy-4′-fluoro B-neomycin analogs. 4′-Deoxyfluorination improves the inhibition profile towards resistant enzymes and renders equally potent antibiotics compared to the parent neomycin B. The 4′-deoxy-4′-fluoro-4′-epi neomycin analogs showed a preferential inhibition over the 4′-deoxy-4′-fluoro neomycin counterpart against the strains of P. aeruginosa carrying a chromosomal APH(3′)-IIb enzyme, known to inactivate the parent aminoglycoside. To the best of our knowledge, this is the first example of a neighboring-group aminoglycoside-modifying enzyme evasion by fluorine substitution. A unique F-G1491 stacking was observed in a co-crystal structure of 4′-deoxy-4′-fluoro-4′-epi neomycin with a bacterial ribosomal RNA A-site.

Graphical abstract: Synthesis, broad spectrum antibacterial activity, and X-ray co-crystal structure of the decoding bacterial ribosomal A-site with 4′-deoxy-4′-fluoro neomycin analogs

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Supplementary files

Article information


Submitted
02 Jun 2014
Accepted
16 Jul 2014
First published
27 Aug 2014

Chem. Sci., 2014,5, 4621-4632
Article type
Edge Article

Synthesis, broad spectrum antibacterial activity, and X-ray co-crystal structure of the decoding bacterial ribosomal A-site with 4′-deoxy-4′-fluoro neomycin analogs

S. Hanessian, O. M. Saavedra, M. A. Vilchis-Reyes, J. P. Maianti, H. Kanazawa, P. Dozzo, R. D. Matias, A. Serio and J. Kondo, Chem. Sci., 2014, 5, 4621
DOI: 10.1039/C4SC01626B

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