ORALS

Aminoglycosides inhibit bacterial growth by binding to the A-site decoding region of the bacterial 16s ribosomal RNA (rRNA) within the 30S ribosomal subunit. Previous work has shown that there is approximately a five-fold difference in the affinity of neomycin for the human A-site model and the E. coli model. The methodology for synthesizing, screening for both ribosomal binding/selectivity and bacterial growth inhibition, and rapid analysis of the data provides a systematic method for identification of bacterial ribosome specific antibacterials that can evade bacterial resistance pathways. We have developed rapid synthetic and screening methods that rapidly identify compounds that discriminate between the two model rRNA structures. Novel potent aminoglycosides that show high selectivity for the bacterial ribosome over mammalian ribosome were identified. Our approach, coupled with a rapid solid phase synthesis of peptidic aminosugars, has identified active aminoglycosides that show large differences in binding affinity for the E. coli A-site vs. the human A-site. Synergistic applications with clinical antibiotics have allowed us to develop novel antimicrobials that can inhibit the growth of multidrug resistant bacteria.

References:
1. Jiang, Li; Watkins, D; Jin, Y; Gong, C; King, Ada; Washington, A; Green, K; Garneau-Tsodikova, S; Oyelere, A; Arya, D. "Rapid Synthesis and Screening of a Peptidic-aminosugar (PA) library targeting rRNA". <i>ACS Chemical Biology</i> <b>2015</b>, May 15,1278-89.
2. Degtyareva NN, Gong C, Story S, Levinson NS, Oyelere AK, Green KD, Garneau-Tsodikova S, Arya DP. Antimicrobial Activity, AME Resistance, and A-Site Binding Studies of Anthraquinone-Neomycin Conjugates. <i>ACS Infect Dis.</i> <b>2017</b> Mar 10;3(3):206-215