Resistance to antibiotics is becoming a major threat to public health and we are facing a risk that available antibiotics may no longer be adequate for treatment of infectious diseases. There is a compelling need for obtaining new antibacterial compounds, and for developing new methods for the production of such compounds. The goal of this study is to develop novel antibacterial agents that specifically bind to the antiterminator element of T box RNAs and inhibit antitermination, thereby inhibiting bacterial cell growth. We have identified a novel regulatory element in bacterial RNA, the T box system antiterminator that is an ideal target for antibacterial drug discovery. This RNA element is widely distributed in Gram-positive bacteria, where it is required for expression of essential aminoacyl-tRNA synthetase (aaRS) genes. Inhibition of T box function results in inhibition of bacterial cell growth, validating this element as a target for antimicrobial agents. Our hypothesis is that the proposed new classes of oxazolidinones and related compounds can be developed into novel antibacterial agents and that the T box antitermination system provides a unique target for antibacterial action with decreased probability of development of resistance. Our preliminary results demonstrate that: a) lead members of this new class of oxazolidinones bind antiterminator RNA with low micromolar to nanomolar affinities and good selectivity for a unique RNA structure;b) lead oxazolidinones compete with tRNA binding to antiterminator RNA;c) lead oxazolidinones have antibacterial activity against Gram-positive bacteria;and d) a lead compound inhibits transcription antitermination in vitro.
Specific Aims are: 1) Synthesize and design new classes of oxazolidinones and related compounds;2) Determine affinity for antiterminator model RNA and determine antibacterial activity of new compounds: and 3) Confirm the mode of action of compounds with antibacterial activity. The structure activity relationships (SAR) determined from Aims 2 and 3 will be used in iterative rounds of compound improvement utilizing molecular modeling, NMR solution structure studies and quantitative SAR analysis to guide the design of compounds.
|Liu, Jia; Zeng, Chunxi; Hogan, Vivian et al. (2016) Identification of Spermidine Binding Site in T-box Riboswitch Antiterminator RNA. Chem Biol Drug Des 87:182-9|
|Zeng, C; Zhou, S; Bergmeier, S C et al. (2015) Factors that influence T box riboswitch efficacy and tRNA affinity. Bioorg Med Chem 23:5702-8|
|Anupam, R; Zhou, S; Hines, J V (2015) Electrophoretic mobility shift assays: analysis of tRNA binding to the T box riboswitch antiterminator RNA. Methods Mol Biol 1240:135-42|
|Zhou, S; Anupam, R; Hines, J V (2015) Fluorescence anisotropy: analysis of tRNA binding to the T box riboswitch antiterminator RNA. Methods Mol Biol 1240:143-52|
|Liu, J; Zeng, C; Zhou, S et al. (2015) Fluorescence assays for monitoring RNA-ligand interactions and riboswitch-targeted drug discovery screening. Methods Enzymol 550:363-83|
|Zhou, S; Means, J A; Acquaah-Harrison, G et al. (2012) Characterization of a 1,4-disubstituted 1,2,3-triazole binding to T box antiterminator RNA. Bioorg Med Chem 20:1298-302|
|Fang, Fang; Vogel, Megan; Hines, Jennifer V et al. (2012) Fused ring aziridines as a facile entry into triazole fused tricyclic and bicyclic heterocycles. Org Biomol Chem 10:3080-91|
|Zhou, Shu; Acquaah-Harrison, George; Jack, Karen D et al. (2012) Ligand-induced changes in T box antiterminator RNA stability. Chem Biol Drug Des 79:202-8|
|Jentzsch, Franziska; Hines, Jennifer V (2012) Interfacing medicinal chemistry with structural bioinformatics: implications for T box riboswitch RNA drug discovery. BMC Bioinformatics 13 Suppl 2:S5|
|Orac, Crina M; Zhou, Shu; Means, John A et al. (2011) Synthesis and stereospecificity of 4,5-disubstituted oxazolidinone ligands binding to T-box riboswitch RNA. J Med Chem 54:6786-95|
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