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http://hdl.handle.net/10397/91312
| Title: | Discovery of antimicrobials targeting RNA polymerase-sigma factor interaction | Authors: | Ye, Jiqing | Degree: | Ph.D. | Issue Date: | 2021 | Abstract: | Transcription is a critical process for bacterial survival. The initiation of bacterial transcription starts with the formation of RNAP holoenzyme by the binding of initiation factor σ to RNAP core enzyme (α2ββ'ω). Therefore, the interruption of the interactions between RNAP core enzyme and σ factor would be a potential and practical target for the design of antimicrobials. In addition, it is revealed that contacts between RNAPβ'CH region and σ2.2 are the most conserved. Previously, compound C3 was identified as a potential β'CH-σ2.2 interaction inhibitor. It showed good inhibitory activity in the binding assay and has potential for further research. To obtain compounds with improved antibacterial activity, we thoroughly explored the structure-activity relationships (SARs) of compound C3, and several derivatives with obviously improved antibacterial activity were identified, including C3-005, C3-087, C3-089, C3-115, C3-128, C3-151, C3-170, C3-174, and C3-176. Especially, C3-087 and C3-151 demonstrated to be the most potent compounds against a panel of pathogens with MICs around 1 μg/mL (~ 2 μM). Subsequently, based on C3-087, a set of 1,4-bis(phenylthio)benzene derivatives were designed and prepared. Amongst, compounds C3-145 and C3-146 exhibited the most potent inhibitory activity against S. aureus with MIC values ≤0.5 μg/mL (≤1μM). Mechanistic studies demonstrated that the compounds exerted their antibacterial activity through the inhibition of RNAP-σ interaction. To further understand the SARs, QSAR models based on the antimicrobial activity of the C3 derivatives were constructed. Besides, docking and molecular dynamic simulations were performed to depict the interactions between the derivatives and β'CH region. | Subjects: | Antibiotics Structure-activity relationships (Biochemistry) Hong Kong Polytechnic University -- Dissertations |
Pages: | xiii, 367 pages : color illustrations |
| Appears in Collections: | Thesis |
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