Development of inhibitors targeting bacterial RNA polymerase holoenzyme formation

Abstract

Antimicrobial resistance (AMR) is a hot topic nowadays. The development of AMR is escalating expeditiously and has provoked serious health issues worldwide. Hence, it is of utmost importance to discover and develop novel antimicrobials. DNA transcription is one of the most crucial processes for bacterial survival. The transcription process is controlled by RNA polymerase (RNAP) and a series of factors. One of the key stages is the formation of RNAP holoenzyme by the protein-protein interactions (PPIs) between RNAP and the σ factor. Previously, compounds C3 and C4 were discovered to be potential antimicrobials acting as PPI inhibitors to block the binding of RNAP and σ factor. In this project, C3 derivatives and C4 analogs were synthesized to examine the structure-activity relationships (SARs) and thereof, to be modified with enhanced inhibitory ability. C4-012, C4-015, C4-017, and C4-018 showed a 32-fold increase in antibiotic activity (MIC = 8 μg/ml) than the originally unmodified structure (MIC = > 256 μg/ml). Docking models were introduced to explain such improvements in terms of the binding behaviors of C4 and the modified C4 derivatives to the β’-CH-σ region.