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, J. Kondo

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4621-4632
Number of pages12
JournalChemical Science
Volume5
Issue number12
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)

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