New antimicrobial therapies are essential to combating the global health crisis caused by tuberculosis (TB): Approximately one third of the world’s population is infected, and drug-resistant Mycobacterium tuberculosis (Mtb) strains are increasing.
The Campbell group is investigating mycobacterial RNA polymerase (RNAP), an enzyme responsible for bacterial transcription and a proven, effective target of antimicrobials. Using cryo-electron microscopy and other tools, she is working to reveal the mechanisms of RNAP and the molecular interactions between RNAP and its inhibitors. In a similar line of research, she is studying the atomic-level interactions between new and existing inhibitors and the SARS-CoV-2 transcription/replication machinery, work that could aid the design of novel drugs for COVID-19. Overall, her goal is to provide structural and functional insights into the nature of these pathogens to guide drug discovery and optimization.
Campbell has shown that mycobacterial RNAP exhibits kinetic properties different from the archetypical Escherichia coli: It initiates transcription at much slower rates, and two transcription factors that are essential in mycobacteria but absent in E. coli, CarD and RbpA, are critical to boosting the rate at which DNA unwinds at promoters.
Campbell’s team was the first to solve the atomic resolution structure of a mycobacteria RNA polymerase, and they are working to determine the structure of the enzyme in conjunction with known, derivative, and entirely new antibiotics, in collaboration with Sean F. Brady and other investigators.
Campbell is also using cryo-EM to determine the structure of Mtb RNAP at near-atomic resolution with various ligands. These “solution” studies have allowed her to observe conformations of the RNA polymerase difficult to capture using other approaches. She is using other imaging techniques to elucidate how the enzyme’s conformations correlate with the kinetic steps of mycobacteria transcription initiation.
More information on Campbell’s research can be found here.