Streptococcus pneumoniae (S. pneumoniae) is a leading bacterial pathogen responsible for various diseases and claiming 1.5 million lives annually. The rising incidence of antibiotic-resistant strains emphasizes the urgency to identify new therapeutic targets. Zinc is an essential micronutrient for survival, but high concentrations can cause toxicity. S. pneumoniae has developed an intricate system to regulate zinc levels, including the Cation Diffusion Facilitator (CDF) protein, CzcD, which facilitates zinc efflux from the cell and protects against zinc toxicity.
This study employs x-ray crystallography and cryo-electron microscopy (cryo-EM) to determine the structure of CzcD in S. pneumoniae and generate nanobodies that can specifically block CzcD activity. The structural characterisation of CzcD will unravel how CzcD facilitates zinc efflux, its interaction with other zinc-regulatory proteins, and how to block it for therapeutic purposes. By targeting CzcD, the nanobodies could disrupt zinc homeostasis in S. pneumoniae, leading to increased sensitivity to zinc toxicity and offer a new therapeutic strategy for antibiotic-resistant strains.
This research will advance our understanding of bacterial zinc homeostasis and its potential as a target for innovative therapeutics against S. pneumoniae and other zinc-dependent bacterial pathogens. Ultimately, this study could lead to the development of a new class of antibacterial agents that target zinc homeostasis.