Klebsiella pneumoniae is a Gram-negative ESKAPE pathogen on the WHO priority list for urgent antibiotic development. Typically associated with nosocomial respiratory and urinary tract infections, there is an increasing emergence of hypervirulent pathotypes in Asia, associated with community acquisition and severe disease presentations including sepsis and liver abscesses. 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.
Zinc is an essential first-row transition metal ion required by all forms of life. However, in excess zinc can mediate substantial toxicity. Bacteria achieve zinc homeostasis using highly tuned uptake and efflux systems. This is of critical importance at the host-pathogen interface where antimicrobial zinc has been shown to contribute to innate immune-mediated killing of invading pathogens. Recent studies have shown that disruption of zinc homeostasis can impair K. pneumoniae virulence in sepsis models of infection, although the underlying molecular basis remains to be elucidated.
Here, we show that K. pneumoniae uses the conserved ATP-binding cassette (ABC) permease ZnuABC as a primary zinc import pathway, and the P-type ATPase ZntA for primary zinc efflux. Unexpectedly, we also identified a novel second ABC permease also involved in zinc import that we have termed ZniABC. The zniABC operon is highly conserved in K. pneumoniae, but absent from other Enterobacteriaceae. The ZnuABC and ZniABC systems appear functionally redundant for zinc uptake, with loss of both systems need to limit zinc import by the cell. Zinc limitation significantly decreases the ability of K. pneumoniae to propagate under high salt and oxidative stress conditions, and inhibits progression of infection in a mouse acute lung model. Collectively, these findings expand our understanding of zinc homeostasis in K. pneumoniae and the Enterobacteriaceae. This knowledge provides a foundation for therapeutic strategies to target and disrupt K. pneumoniae metal homeostasis.