Assessing Paracoccus denitrificans zinc metallochaperone AztD as a potential novel antibiotic drug target

Abstract

Zinc is an important cofactor required for the catalytic activity and structural stability of enzymes. Additionally, zinc plays critical roles in host‐pathogen interactions during bacterial infection. As such, zinc homeostasis and its regulation are vital for every organism. Bacteria use ATP Binding Cassette (ABC) transporters to acquire zinc from their extracellular surroundings. In Paracoccus denitrificans, the ABC transporter consists of a cytoplasmic ATPase (AztA), a transmembrane permease (AztB), a periplasmic solute binding protein (AztC), and a metallochaperone (AztD). The P. denitrificans zinc import system is closely related to that of carbapenem resistant Enterobacteriaceae (CRE), a group of pathogenic organisms considered an urgent threat to human health by the Centers for Disease Control. These zinc import system proteins are necessary for bacterial virulence, have no known homologs in eukaryotes, and are conserved in human pathogens. Thus, this study aims to assess AztD as a potential novel antibiotic drug target. Current work involves using site‐directed mutagenesis to delete the N‐terminal domain of AztD in order to further understand its role in zinc binding and transfer to AztC. Future experiments include screening for pore blocking molecules that could act as zinc transfer inhibitors.Support or Funding InformationNational Institutes of Health 1R01GM122819‐01A1