Toxicity modulation, resistance enzyme evasion, and A-site X-ray structure of broad-spectrum antibacterial neomycin analogs

Juan Pablo Maianti, Hiroki Kanazawa, Paola Dozzo, Rowena D. Matias, Lee Ann Feeney, Eliana S. Armstrong, Darin J. Hildebrandt, Timothy R. Kane, Micah J. Gliedt, Adam A. Goldblum, Martin S. Linsell, James B. Aggen, Jiro Kondo, Stephen Hanessian

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fl uorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel β,β-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs.

Original languageEnglish (US)
Pages (from-to)2067-2073
Number of pages7
JournalACS Chemical Biology
Volume9
Issue number9
DOIs
StatePublished - Sep 19 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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