Zinc displacement and metabolic interference: cobalt ion-mediated therapy for broad-spectrum CRKP-resistant pneumonia via inhalable microspheres

Currently, broad-spectrum carbapenem-resistant Klebsiella pneumoniae (CRKP) infectious pneumonia remains clinically difficult to treat. This study develops inhalable microspheres (SCM) loaded with meropenem (MEM), fabricated via microfluidics by cross-linking sodium alginate with Co2+, for synergistic therapy against drug-resistant bacterial pneumonia. The core discovery lies in Co2+’s dual mechanism of action, which addresses both metallo- and serine-mediated carbapenem resistance. Co2+ irreversibly inhibits NDM-1 by displacing its active-site Zn2+ to restore MEM’s bactericidal effect. For KPC-2-producing CRKP, Co2+ disrupts bacterial iron/sulfur metabolism, induces energy crisis and nutrient starvation, and reprograms bacterial metabolism toward inefficient fermentation. SCM shows potent in vitro activity against target strains and anti-biofilm capacity. In mouse models, treatment with inhaled SCM reduces bacterial levels in the lungs, improves survival rates, and lessens inflammatory damage. It also regulates the immune response in the lungs. Specifically, this therapy prevents the excessive migration of neutrophils to the lungs, inhibits excessive M1 polarization of macrophages and promotes their conversion to the M2 phenotype, while reverses T-cell exhaustion and maintains the homeostasis of NK cells. Transcriptome analysis confirms reversed infection-induced dysregulation and enhanced genes related to tissue repair. This work clarifies Co2+’s dual role (both an enzyme inhibitor and a metabolic disruptor) and provides an inhalable co-delivery strategy for CRKP. The global rise of carbapenem-resistant bacteria, driven by enzymes such as KPC-2 and OXA-48 as well as metallo-β-lactamases, poses a major challenge to antibiotic therapy. Here, the authors develop a cobalt-based microsphere platform for the delivery of meropenem, leveraging Co²⁺ as a metal-based resistance breaker to overcome multiple resistance mechanisms. In a mouse model of drug-resistant pneumonia, the treatment improved survival, reduced bacterial burden, and mitigated excessive inflammation, highlighting a promising strategy for combating multidrug-resistant infections.