Poster abstracts

Poster number 56 submitted by Md Ismail Hossain

Modulation of T-box riboswitch function by analogs of 4,5-disubstituted oxazolidinones

Md Ismail Hossain (Chemistry & Biochemistry, Ohio University), Ali Aldhumani (Chemistry & Biochemistry, Ohio University), Rumita Laha (Chemistry & Biochemistry, Ohio University), Jennifer V. Hines (Chemistry & Biochemistry, Ohio University)

Abstract:
The number of antibiotics that were once used efficiently to treat bacterial infections are becoming resistant at an alarming rate. Multi-drug resistant bacteria are now common and may cause the death of individuals with simple infections. Fighting against the super-bugs globally has become a challenge. Fortunately, new drug targets like the T-box riboswitch have been identified in bacteria, which are not found in the human genome. These non-coding regulatory RNAs are found in the 5´ untranslated regions of the bacterial mRNA which codes for proteins crucial for their survival. The T-box riboswitch controls gene expression through interaction with its natural ligand tRNA, and the antiterminator RNA element of the T-box riboswitch is highly conserved.1 We are investigating new classes of compounds targeting this regulatory RNA element. Previous studies of 4,5-disubstituted oxazolidinones showed promising binding specificity with different antiterminator model RNAs.2 Analogs of these compounds were tested to determine their ability to a) modulate the stability of the antiterminator RNA, b) disrupt the antiterminator binding to the tRNA, and c) inhibit the T-box riboswitch function using different fluorescence monitored assays developed in our lab.3,4 Four of these compounds disrupted the tRNA-antiterminator complex formation, three of which also inhibited riboswitch function, indicating possible antiterminator specific inhibition. The results indicate the potential to discover novel molecules that would modulate the riboswitch function with significant binding affinity and specificity with the antiterminator RNA.

References:
1. Kreuzer, Kiel D., and Tina M. Henkin. "The T box riboswitch: tRNA as an effector to modulate gene regulation." Microbiology spectrum 6, no. 4 (2018).
2. Anupam, Rajaneesh, Abhijit Nayek, Nicholas J. Green, Frank J. Grundy, Tina M. Henkin, John A. Means, Stephen C. Bergmeier, and Jennifer V. Hines. "4, 5-Disubstituted oxazolidinones: high affinity molecular effectors of RNA function." Bioorganic & medicinal chemistry letters 18, no. 12 (2008): 3541-3544.
3. Zhou, Shu, George Acquaah‐Harrison, Karen D. Jack, Stephen C. Bergmeier, and Jennifer V. Hines. "Ligand‐Induced Changes in T Box Antiterminator RNA Stability." Chemical biology & drug design 79, no. 2 (2012): 202-208.
4. Zeng, C., S. Zhou, S. C. Bergmeier, and J. V. Hines. "Factors that influence T box riboswitch efficacy and tRNA affinity." Bioorganic & medicinal chemistry 23, no. 17 (2015): 5702-5708.

Keywords: Riboswitch, Drug discovery, 4,5-disubstituted oxazolidinones