Antimicrobial resistance has been identified as an emerging threat to global health. Despite the implementation of many programs to slow the development of antimicrobial resistance there is still a need to develop antibiotics that are of novel class and have a novel mechanism of action. Transcription is essential for all organisms and despite the high structural conservation of the active site, the regulation of transcription is not well conserved across the kingdoms of life. The initial step of transcription requires the assembly of the RNA polymerase holoenzyme through the binding of a sigma factor to the core enzyme complex. By inhibiting this protein-protein interaction all transcription in the cell can be inhibited leading to a loss of cell viability.
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 assembly 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 including Methicillin ResistantĀ Staphylococcus aureus (MRSA) with MICs as low as 3.1 Ī¼M. 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, establishing a platform for the development of a series of new antibacterial drugs with an established mode of action.