Year: 2016
Type: article
Abstract: In cells, ribosomes translate the genetic information in messenger RNA to synthesize proteins.Aminoglycosides (AGs) represent a very large group of antimicrobials that target this crucial process of translation in bacteria.They target helix h44 of 16S rRNA and H69 of 23S rRNA, and cause miscoding, inhibit mRNA-tRNA translocation and inhibit ribosome recycling.The role of each of the two AG binding sites in inhibition of translocation has remained unclear.Binding of AGs to h44 is believed to stabilize A site tRNA and cause miscoding and inhibition of translocation.Binding of AG to H69 is suggested to inhibit ribosome recycling.In Chapter 2 I analyzed the role of the two AG binding sites to inhibition of mRNA-tRNA translocation.My data suggest that h44 site is central to the activity of translocation inhibition of NEO and TOB, representatives of 4,5-and 4,6-substituted 2-deoxystrptamine AGs.By contrast, the H69 site plays no role in translocation inhibition by TOB and only a minor role in translocation inhibition by NEO.This work sheds light on the roles of the two AG binding sites in AG activity in ribosomes.With the emergence of AG-resistant bacterial strains, the need to develop novel AGs with improved bacterial ribosome-targeting capability and enhanced antimicrobial activity is more and more pressing.In Chapter 3 of this work, I evaluated 37 novel tobramycin (TOB) derivatives with various thioether iii substituents at the 6''-position.Thirteen of these displayed better antibacterial activity than the parent TOB while retaining ribosome-targeting specificity.Analysis of these compounds in vitro revealed three with clearly enhanced ribosome-targeting activity.These compounds are also poorer substrates of AGmodifying enzymes compared to TOB.This study identified promising antibiotic candidates and a possible general strategy to increase the efficacy of ribosometargeting antibiotics.Chapter 4 describes my discovery that eleven AG derivatives can inhibit DNA polymerases.Especially, they are strong reverse transcriptase inhibitors.My results showed that these drugs represent a new class of potent RT inhibitors (IC 50 values of 0.3-40 µM), which act through a site distinct from the NNRTI binding site.This work identified a novel group of promising anti-HIV drug candidates, and a possible general strategy to produce similar anti-HIV drugs. Special thanks to my advisor Dr. Kurt Fredrick
Author: Hongkun Zhu
Institution: The Ohio State University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2595159416