Toxicity Modulation, Resistance Enzyme Evasion, and A-Site X-ray Structure of Broad-Spectrum Antibacterial Neomycin Analogs
Citations Over TimeTop 16% of 2014 papers
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 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 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.
Related Papers
- → Design, Synthesis, and Antibacterial Activities of Neomycin−Lipid Conjugates: Polycationic Lipids with Potent Gram-Positive Activity(2008)97 cited
- → EFFECTS OF GENTAMICIN, NEOMYCIN AND TOBRAMYCIN ON RENAL CALCIUM AND MAGNESIUM HANDLING IN TWO RAT STRAINS(1994)19 cited
- → Design, Chemical Synthesis, and Antibacterial Activity of Kanamycin and Neomycin Class Aminoglycoside Antibiotics(2007)14 cited
- → Cross-sensitivity and aminoglycoside antibiotics(1973)4 cited
- → Decreased Cellular Toxicity of Neomycin in a Clonal Cell Line Isolated from LLC-PK1(1993)3 cited