American Chemical Society
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Toward Overcoming Staphylococcus aureus Aminoglycoside Resistance Mechanisms with a Functionally Designed Neomycin Analogue

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journal contribution
posted on 2011-12-08, 00:00 authored by Stephen Hanessian, Alexandre Giguère, Justyna Grzyb, Juan Pablo Maianti, Oscar M. Saavedra, James B. Aggen, Martin S. Linsell, Adam A. Goldblum, Darin J. Hildebrandt, Timothy R. Kane, Paola Dozzo, Micah J. Gliedt, Rowena D. Matias, Lee Ann Feeney, Eliana S. Armstrong
Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(l)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50). Antibiotic 1 displayed >64 fold improvement in MIC50 and MIC90 against this MRSA collection when compared to the clinically relevant aminoglycosides amikacin and gentamicin. The synthesis was achieved in six steps and 15% overall yield.