Transcription is essential for the existence of life, and the enzyme RNA polymerase (RNAP) catalysing this process is found in all cellular life forms. The Firmicutes are gram-positive bacteria important medically and industrially. Several clinically significant pathogens, ranging from opportunistic pathogens to biowarfare agents, are Firmicutes. They are also a major group in antibiotic resistant infections. All these make RNAP a prime target for future antimicrobials.
Cryo-electron microscopy (cryo-EM) has recently been going through a paradigm shift, solidifying its place among the structural biology methods. Several high resolution cryo-EM structures of transcription complexes published recently from bacterial and eukaryotic organisms proved cryo-EM as a perfect fit for determining the structures of such complexes. Such structures not only reveal mechanistic details of how such bio-nano-machines work, but also facilitate development of novel antimicrobial drugs targeting them.
Being the smallest multi-subunit RNAP known, the RNAP of Firmicutes is significantly different than other organisms’. Moreover, Firmicutes encode a number of transcription factors which are not found in other organisms. There are still no high-resolution structures of any Firmicute RNA polymerases available. In this study, we determined the high-resolution cryo-EM structures of the core RNAP and also RNAP in complex with a novel transcription factor (at ~3 Å), from a model Firmicute. The comparison of these structures provides structural and mechanistic insights into Firmicute transcription. These structures are also expected to facilitate the development of new antimicrobial compounds against this important group of pathogens in the future.