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Publication Abstract from PubMed

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 fluorinated 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 beta,beta-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.

Toxicity modulation, resistance enzyme evasion, and A-site X-ray structure of broad-spectrum antibacterial neomycin analogs.,Maianti JP, Kanazawa H, Dozzo P, Matias RD, Feeney LA, Armstrong ES, Hildebrandt DJ, Kane TR, Gliedt MJ, Goldblum AA, Linsell MS, Aggen JB, Kondo J, Hanessian S ACS Chem Biol. 2014 Sep 19;9(9):2067-73. doi: 10.1021/cb5003416. Epub 2014 Jul, 14. PMID:25019242^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.