Investigator: Khadine Higgins, Salve Regina University
Mentor: Gongquin Sun, University of Rhode Island

Title: Exploring Structure Function Relationships in KmtR
Scientific Theme: Molecular Toxicology
Award: Early Career Development (2016-2018)

Abstract: The long term goal of this work is aimed at understanding why Mycobaterium tuberculosis (M. tuberculosis) requires two Ni(II)- and Co(II)-responsive metalloregulators associated with the export of Ni(II) and Co(II) and how these two regulators differ. M. tuberculosis is the causative agent of tuberculosis, which is responsible for approximately two million deaths each year. The bacteria encodes several metal transport systems that are critical for its survival in phagosomes where the metal concentrations are always changing. KmtR is the second Ni(II)-and Co(II)-responsive metalloregulator in the M. tuberculosis. Nothing is known about why this metalloregulator is responsive to Ni(II) and Co(II) binding and if KmtR is capable of binding to other first-row transition metals. This work seeks to determine the metal site structures in KmtR and the respective metal binding affinities. These studies are aimed at elucidating how the metal site structures relate to the function of KmtR. The need for an understanding of how pathogenic bacteria are able to maintain intracellular concentrations of metal ions is of utmost importance as the number of drug resistant strains of these bacteria continue to increase. The fact that there are no known Ni(II) dependent metalloenzymes in humans makes the Ni(II) trafficking pathway in M. tuberculosis an attractive candidate for new strategies to combat this deadly human pathogen.

Human Health Relevance: Nearly two million people die each year from tuberculosis. With an increase in the number of drug-resistant strains of Mycobacterium tuberculosis new antibiotic therapies that target essential metabolic pathways are critical. The acquisition of metals including Ni(II) and Co(II) is important for its ability to survive host killing mechanisms