Siderophore-Functionalized Nanodrug for Treating Antibiotic-Resistant Bacteria

Abstract

The development of nanodrugs targeting multidrug-resistant bacteria, while sparing the beneficial constituents of the microbiome, has emerged as a promising approach to combat disease and curb the rise of antimicrobial resistance. In this investigation, we devised a siderophore-functionalized nanodrug based on a gold nanoparticle construct (AuNP-NSC; Gold nanoparticle_N-heterocyclic_Siderophore_Cyanine7), offering an innovative treatment modality against drug-resistant bacterial pathogens. As a proof of concept, the efficacy of this nanodrug delivery and antimicrobial therapy was evaluated against the notoriously resistant bacterium P. aeruginosa. N-Heterocyclic carbenes (NHCs) exhibit a strong affinity for transition metals, forming highly stable complexes resistant to ligand displacement. The entry of siderophore-conjugated nanodrugs into bacteria is facilitated through specific receptors on the outer membrane. In our study, AuNP-NSC was specifically targeted and imported into resistant Gram-negative P. aeruginosa via binding with ferric iron. Treatment with the developed nanodrug significantly inhibited the proliferation of antibiotic-resistant P. aeruginosa, reducing bacterial counts by more than 95% and mitigating drug resistance. Furthermore, AuNP-NSC markedly diminished P. aeruginosa-induced skin lesions and forestalled systemic organ failure triggered by secondary sepsis in mouse models. These findings underscore the potential of nanodrugs as specialized therapeutic agents for the management of antibiotic-resistant bacterial infections.