Intracellular Zn²⁺ dynamics regulate cefiderocol resistance in Klebsiella pneumoniae

Aims: The worldwide spread of carbapenem-resistant Klebsiella pneumoniae (CRKP) has posted a global threat. Treatment options for CRKP are limited, especially for strains producing New Delhi metallo-β-lactamase (NDM). The emergence of the siderophore antibiotic cefiderocol has brought hope; however, recent clinical and research data show that NDM-producing K. pneumoniae have a high rate of resistance to cefiderocol, and the reason remains unclear. Methods: This study focused on the dynamic changes in K.pneumoniae under host nutritional immunity and cefiderocol stress. It identified one of the main reasons for the strong cefiderocol resistance in NDM-producing strains. Further studies found that the JNMCOFLA_01041 gene plays an important role in this process and is crucial for cefiderocol resistance and virulence in K.pneumoniae. Results: Under host nutritional immunity and cefiderocol stress, K.pneumoniae is exposed to increasing oxidative stress. This oxidative stress results in a dynamic pattern of rapid increases in intracellular Zn²⁺ concentrations. This autonomous changes in Zn²⁺ levels in response to cefiderocol challenge can rapidly increase NDM enzyme activity and enhance the MIC, which may be one of the main reasons for the high cefiderocol minimal inhibit concentration (MIC) in NDM-producing strains. Further study identified a key gene, JNMCOFLA_01041, for Zn²⁺ and hemin absorption in K. pneumoniae. The Zn²⁺ acquisition function plays an important role in oxidative stress resistance, NDM activity, metabolism, and even pathogenicity. Conclusions: Taken together, our research highlights the impact of dynamic changes in bacterial metal ion concentrations on bacterial survival and drug resistance under complex host conditions. It emphasizes that, while using antimicrobial drugs, monitoring and regulating changes in the bacterial internal environment under pathological conditions is crucial for maximizing anti-infective efficacy. Furthermore, JNMCOFLA_01041 could be a target of novel drug and vaccine development.