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.
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