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Periplasmic Zinc Management and Homeostasis in Paracoccus Denitrificans

Yukl, Erik T
New Mexico State University
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ABSTRACTThe prevalence of antibiotic resistance among pathogenic bacteria has become a major healthconcern and has spurred the search for novel antibiotic targets. A particularly promising target isthe superfamily of bacterial ATP-binding cassette (ABC) transporters, which couple the hydrolysisof ATP to the transport of a wide variety of solutes across the cell membrane. Bacterial ABCtransporters work in conjunction with a high affinity solute binding protein (SBP) that specificallybinds substrate and delivers it to the transporter. In Salmonella enterica and Streptococcuspneumoniae among others, disruption of genes encoding ABC transporters and SBPs specific forZn dramatically attenuates virulence in animal models, highlighting these systems as potent drugtargets. We have identified two Zn-specific ABC transporter operons in Paracoccus denitrificans,ZnuABC and AztABCD, and have characterized a hitherto hypothetical protein (AztD) that acts asa Zn chaperone, directly transferring Zn to the SBP of that system (AztC). This project will utilizeP. dentrificans as a model for highly homologous systems in human pathogens belonging to thecarbapenem-resistant Enterobacteriacaea (CRE). These organisms are associated with broad-spectrum antimicrobial resistance and are the causative agents of potentially deadly nosocomialinfections. We will determine the precise mechanism of metal binding and transfer for AztC andAztD proteins from P. denitrificans and the CRE pathogen Citrobacter koseri using structural andbiophysical techniques. The physiological roles of the Azt and Znu systems will be determined bymaking genetic knockouts of these genes in P. denitrficans and characterizing growth deficientphenotypes in Zn-limited medium. High-resolution structural information combined with in vivofunctionality will yield new insight into the mechanisms of transition metal import in bacteria andpotentially provide a basis for the rational design of metal uptake inhibitors as antibiotics for multi-drug resistant pathogens. !
Funding Source
Nat'l. Inst. of General Medical Sciences
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Escherichia coli
Antimicrobial Resistance