STRUCTURAL STUDIES ON THE ROLE OF ZINC IN BACTERIAL PROLIFERATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The most successful antibiotics act as mechanism-based inhibitors of specific cellular processes involved in bacterial proliferation and virulence. Mechanistic investigations of VanX (vancomycin resistance) and the metallo-?-lactamases (penicillin resistance), which play defensive roles for an individual bacterium, and of the AHL-lactonase, which plays a prominent role in intercellular bacterial communication (quorum quenching), controlling virulence, are in process. The common thread to these systems is their dependence on Zn(II) for activty, and their ability to bind cobalt at the active site as the high-spin (hs) Co(II) ion. Each represents an important clinical target. We have used x-ray absorption spectroscopy (XAS) and multi-frequency electron paramagnetic resonance (EPR) to study both the native Zn and Co-substituted forms of the aforementioned enzymes in their resting states. We have recently begun to study catalytically relevant intermediates using rapid-freeze-quench techniques. More detailed magnetic resonance experiments will probe more subtle structural details, in order to establish a structural timeline for catalysis.