Poster abstracts

Poster number 3 submitted by Ali Aldhumani

Polyamine modulation of T-box riboswitch function for antibacterial drug discovery

Ali H. Aldhumani (Department of Chemistry & Biochemistry, Ohio University, Athens Ohio), Hannah Cherry (Department of Chemistry & Biochemistry, Ohio University, Athens Ohio), Jennifer V. Hines (Department of Chemistry & Biochemistry, Ohio University, Athens Ohio)

Abstract:
Aliphatic amine and polyamine cations are known to be bioavailable in high concentrations in the presence of both DNA and RNA implying a nonspecific interaction. However, there is growing evidence that biogenic amines may serve a specific structural role by stabilizing RNA through the formation of nucleotide- and structure-specific interactions. The effect of amines and polyamines on the function of the T-box riboswitch will be presented. The T-box riboswitch is typically found in the 5′-noncoding region of Gram-positive bacterial mRNAs where it regulates gene expression in response to cognate tRNA aminoacylation ratios. Previous studies indicate that biologically unfeasible levels of Mg2+ are required for the T-box riboswitch to optimally function in vitro. Our results show that in the absence of Mg2+, biogenic amines spermidine, spermine, and cadaverine can compensate to facilitate binding of the tRNA to the T-box riboswitch antiterminator element. There is a reduced dependency on Mg2+ with the tRNA-antiterminator complex forming at even 0 mM Mg2+ when in the presence of these polyamines.

Identification and characterization of amines as potential co-factors or modulators of the T-box riboswitch will assist in the development of a novel potential drug pharmacophore as well as a more thorough understanding of the druggability of this riboswitch. Due to the increased resistance to antibiotics, it has become imperative to investigate novel drug targets such as the T-box riboswitch. Based on the observed agonist activity with the biogenic amines, we have designed a series of cationic peptides to potentially identify an inhibitor of the riboswitch. The peptides were designed based on molecular docking studies and one peptide has been identified which modulates tRNA binding to the antiterminator and also in vitro transcription function of the T-box riboswitch.

Keywords: Polyamine, Peptide, T-box Riboswitch