title: Rapid synthesis, RNA binding, and antibacterial screening of a peptidic-aminosugar (PA) library.
abstract: A 215-member mono- and diamino acid peptidic-aminosugar (PA) library, with neomycin as the model aminosugar, was systematically and rapidly synthesized via solid phase synthesis. Antibacterial activities of the PA library, on 13 bacterial strains (seven Gram-positive and six Gram-negative bacterial strains), and binding affinities of the PA library for a 27-base model of the bacterial 16S ribosomal A-site RNA were evaluated using high-throughput screening. The results of the two assays were correlated using Ribosomal Binding-Bacterial Inhibition Plot (RB-BIP) analysis to provide structure-activity relationship (SAR) information. From this work, we have identified PAs that can discriminate the E. coli A-site from the human A-site by up to a 28-fold difference in binding affinity. Aminoglycoside-modifying enzyme activity studies indicate that APH(2″)-Ia showed nearly complete removal of activity with a number of PAs. The synthesis of the compound library and screening can both be performed rapidly, allowing for an iterative process of aminoglycoside synthesis and screening of PA libraries for optimal binding and antibacterial activity for lead identification.
authors.affiliation: †Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, South Carolina 29634, United States.
authors.forename: Liuwei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: ‡NUBAD, LLC, Greenville, South Carolina 29605, United States.
authors.forename: Derrick
authors.initials: D
authors.lastname: Watkins
authors.affiliation: †Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, South Carolina 29634, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: †Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, South Carolina 29634, United States.
authors.forename: Changjun
authors.initials: C
authors.lastname: Gong
authors.affiliation: ‡NUBAD, LLC, Greenville, South Carolina 29605, United States.
authors.forename: Ada
authors.initials: A
authors.lastname: King
authors.affiliation: §School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
authors.forename: Arren Z
authors.initials: AZ
authors.lastname: Washington
authors.affiliation: ∥College of Pharmacy, Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0596, United States.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.affiliation: ∥College of Pharmacy, Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0596, United States.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.affiliation: §School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
authors.forename: Adegboyega K
authors.initials: AK
authors.lastname: Oyelere
authors.affiliation: †Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, South Carolina 29634, United States.|‡NUBAD, LLC, Greenville, South Carolina 29605, United States.
authors.forename: Dev P
authors.initials: DP
authors.lastname: Arya
mesh_terms: D000606:Amino Sugars / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D002240:Carbohydrate Sequence; D057166:High-Throughput Screening Assays; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D019151:Peptide Library; D012313:RNA / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000606:Amino Sugars; D000900:Anti-Bacterial Agents; D019151:Peptide Library; D012313:RNA