title: Toward Overcoming Staphylococcus aureus Aminoglycoside Resistance Mechanisms with a Functionally Designed Neomycin Analogue.
abstract: 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.
authors.affiliation: Department of Chemistry, Université de Montréal , C.P. 6128, Succ. Centre-Ville, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
authors.affiliation: Department of Chemistry, Université de Montréal , C.P. 6128, Succ. Centre-Ville, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Giguère
authors.affiliation: Department of Chemistry, Université de Montréal , C.P. 6128, Succ. Centre-Ville, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Justyna
authors.initials: J
authors.lastname: Grzyb
authors.affiliation: Department of Chemistry, Université de Montréal , C.P. 6128, Succ. Centre-Ville, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Maianti
authors.affiliation: Department of Chemistry, Université de Montréal , C.P. 6128, Succ. Centre-Ville, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Saavedra
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: Aggen
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Linsell
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Goldblum
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Hildebrandt
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Kane
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: Paola
authors.initials: P
authors.lastname: Dozzo
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Gliedt
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: Rowena D
authors.initials: RD
authors.lastname: Matias
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Feeney
authors.affiliation: Achaogen Inc. , 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, United States.
authors.forename: Eliana S
authors.initials: ES
authors.lastname: Armstrong
keywords: Aminoglycoside; MRSA; antibiotics; deoxygenation; enzymatic modification; neomycin analogues; resistance