title: Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity.
abstract: The nucleotides comprising the ribosomal decoding center are highly conserved, as they are important for maintaining translational fidelity. The bacterial A-site has a small base variation as compared with the human analogue, allowing aminoglycoside (AG) antibiotics to selectively bind within this region of the ribosome and negatively affect microbial protein synthesis. Here, by using a fluorescence displacement screening assay, we demonstrate that neomycin B (NEO) dimers connected by L-arginine-containing linkers of varying length and composition bind with higher affinity to model A-site RNAs compared to NEO, with IC50values ranging from ~40-70 nM, and that a certain range of linker lengths demonstrates a clear preference for the bacterial A-site RNA over the human analogue. Furthermore, AG-modifying enzymes (AMEs), such as AGO-phosphotransferases, which are responsible for conferring antibiotic resistance in many types of infectious bacteria, demonstrate markedly reduced activity against several of the L-arginine-linked NEO dimersin vitro. The antimicrobial activity of these dimers against several bacterial strains is weaker than that of the parent NEO.
authors.affiliation: Clemson University, Department of Chemistry, Clemson, SC, 29634, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: NUBAD, LLC, Greenville, SC, 29605, USA.
authors.forename: Derrick
authors.initials: D
authors.lastname: Watkins
authors.affiliation: NUBAD, LLC, Greenville, SC, 29605, USA.
authors.forename: Natalya N
authors.initials: NN
authors.lastname: Degtyareva
authors.affiliation: University of Kentucky, Department of Pharmaceutical Sciences, 789 South Limestone Street, Lexington, KY, 40536-0596, USA. ; Tel: 859-218-1686.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.affiliation: NUBAD, LLC, Greenville, SC, 29605, USA.
authors.forename: Meredith N
authors.initials: MN
authors.lastname: Spano
authors.affiliation: University of Kentucky, Department of Pharmaceutical Sciences, 789 South Limestone Street, Lexington, KY, 40536-0596, USA. ; Tel: 859-218-1686.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.affiliation: Clemson University, Department of Chemistry, Clemson, SC, 29634, USA; NUBAD, LLC, Greenville, SC, 29605, USA.
authors.forename: Dev P
authors.initials: DP
authors.lastname: Arya
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