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Project

Structure-based design of ribonucleoside triphosphate (rNTP) analogs targeting bacterial RNA polymerases

The emergence of antibiotic resistance is among the leading public health concern worldwide. While the restricted use of antibiotic is adopted as a general practice to minimize the emergence of resistant bacteria, the discovery of new drugs is of urgent need. Inhibitors targeting bacterial RNA polymerase (RNAP) are used for treating several bacterial infections. Rifampicin is used to treat infections caused by mycobacteria tuberculosis and leprosy, and by other Gram-negative and Gram-positive bacteria including deadly inhalational anthrax. Another RNAP inhibitor fidaxomicin is used for treating Clostridium difficile infection.Blocking the binding of ribonucleoside triphosphate (rNTP) substrate to bacterial RNAP can lead to the discovery of a new class of antibiotics. Our current NTP analogs have shown promises by inhibiting RNAP at low micromolar concentration. A structure-guided approach will be employed to design highly specific and potent inhibitors of bacterial RNAPs. We have been engaged in (i) structural studies of RNAPs from Mycobacterium tuberculosis (Mtb) by single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography, and (ii) design and synthesis of various nucleoside analogs through in-house and international collaborations. In this two-year project, we propose to obtain higer-resolution structures of the large molecular machine Mtb RNAP using X-ray crystallography and cryo-EM, and obtain the structures in complex with our inhibitor hits.  This study will establish an effective structure-based drug design platform for developing rNTP analogs as antibacterial agents.Publications1.Lin et al. Structural basis of Mycobacterium tuberculosis transcription and transcription inhibition. Mol. Cell 66:169-179 (2017).2.Lin et al. Structural basis of transcription inhibition by fidaxomicin (lipiarmycin A3). Mol. Cell 70:60-71 (2018).
Date:16 Oct 2018 →  30 Sep 2020
Keywords:rNTP
Disciplines:Microbiology, Systems biology, Laboratory medicine