Klebsiella pneumoniae is a WHO priority pathogen that can mediate pneumonia, urinary tract infections and sepsis. It is a frequent nosocomially acquired infection, and high levels of antibiotic resistance amongst the species presents a major clinical challenge. The emergence of hypervirulent K. pneumoniae pathotypes in Asia, associated with community acquisition and severe disease presentations, is complicating infection control and treatment options. Antimicrobial resistance and hypervirulence are horizontally transferred in K. pneumoniae, and further dissemination and co-occurrence of these traits presents a global threat to control of this pathogen. In the absence of vaccines, and against a background of increasing multi-drug resistance in clinical isolates, new therapeutic options to control K. pneumoniae infections are critically important for human health.
Here, we investigated K. pneumoniae homeostasis of zinc, an essential metal ion for survival at the host-pathogen interface. Zinc is estimated to be used by ~8% of the K. pneumoniae proteome, where it facilitates crucial cellular processes such as protein synthesis and regulation of central metabolism. However, zinc can also be highly toxic in excess, due to its tendency to displace other essential metal cofactors from their cognate metalloproteins. As such, intracellular zinc levels need to be tightly regulated to ensure survival. We report the identification and characterisation of the primary zinc homeostatic pathways in K. pneumoniae. By combining elemental analysis with molecular microbiological approaches, we show that the ATP-binding cassette (ABC) permease znuABC is the primary zinc import pathway, while the P-type ATPase zntA is responsible for efflux of excess zinc. Mutation of either pathway alters cellular zinc levels and perturbs the bacterial growth in the presence of zinc stress. Disruption of K. pneumoniae zinc homeostasis also impacts virulence associated properties, such as biofilm formation. Our findings demonstrate the crucial role of zinc homeostasis in K. pneumoniae and underscore the potential for disruption of bacterial zinc homeostasis as an antimicrobial therapeutic strategy.