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New antimicrobial therapies are essential to combating the global health crisis caused by Tuberculosis: Approximately one third of the world’s population is infected, and drug-resistant Mycobacterium tuberculosis (Mtb) strains are increasing.

Campbell is investigating mycobacterial RNA polymerase (RNAP), an enzyme responsible for bacterial transcription and a proven, effective target of antimicrobials. Using cryo-EM and other tools, she is working to reveal the mechanisms of RNAP and the molecular interactions between RNAP and its inhibitors. Her goal is to provide structural and functional insights to guide TB 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 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 never before observed in nature. 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.