Antibiotic-resistant bacteria raise serious global health concern. New targets need to be identified and antibiotics with new modes of action are urged to be developed. Bacterial transcription is a valid but underutilized target for antibacterial drug development. Proteins NusB and NusE are bacterial transcription factors required for the formation of an antitermination complex to carry out rRNA synthesis. A series of diaryl compounds with specific binding to NusB, which mimic the interaction conserved across bacteria between NusB and NusE, have been rationally designed and efficiently synthesized. The inhibitory effects of diaryl compounds to NusB were proved from different chemical biology aspects. The protein structural changes of inhibitor-treated NusB are studied with circular dichroism and isothermal titration calorimetry. The crystal structures of the NusB-compound complexes are to be obtained through X-ray crystallography. The <i>Bacillus subtilis</i> cells containing GFP-tagged NusB are treated with two representative diaryl compounds and the morphological changes of NusB observed using the confocal fluorescence microscopy. Images of the treated cells with changed morphology demonstrated the inhibitory effects of the bacterial transcription targeting inhibitors on the bacteria. In summary, we identified a new class of small molecular antimicrobial agents targeting bacterial transcription, and confirmed the mechanism of action. The suitable lead compounds will undergo in vivo studies in the near future.<br/>

Study of a new class of diaryl compounds as bacterial transcription inhibitors for antibacterial agent discovery

2019 Fall National Meeting

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