期刊
BIOORGANIC CHEMISTRY
卷 118, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.105481
关键词
DNA Transcription inhibition; Antibacterial; Indoles; RNA polymerase
资金
- National Health and Medical Research Council Australia (NHMRC) [APP1021479]
- UNSW Sydney
A series of hybrid compounds incorporating anthranilic acid and activated 1H-indoles were designed to target bacterial RNA polymerase holoenzyme formation using computational docking. Experimental results showed that these compounds demonstrated activity against a range of pathogenic bacteria, potentially serving as new antibacterial drugs.
A series of hybrid compounds that incorporated anthranilic acid with activated 1H-indoles through a glyoxylamide linker were designed to target bacterial RNA polymerase holoenzyme formation using computational docking. Synthesis, in vitro transcription inhibition assays, and biological testing of the hybrids identified a range of potent anti-transcription inhibitors with activity against a range of pathogenic bacteria with MICs as low as 3.1 mu M. A structure activity relationship study identified the key structural components necessary for inhibition of both bacterial growth and transcription. Correlation of in vitro transcription inhibition activity with in vivo mechanism of action was established using fluorescence microscopy and resistance passaging using Grampositive bacteria showed no resistance development over 30 days. Furthermore, no toxicity was observed from the compounds in a wax moth larvae model, establishing a platform for the development of a series of new antibacterial drugs with an established mode of action.
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