Antimicrobial Delivery Using Metallophore-responsive Dynamic Nanocarriers

The increasing prevalence of multidrug-resistant (MDR) pathogens has promoted the development of innovative approaches, such as drug repurposing, synergy, and efficient delivery, in complement to traditional antibiotics. In this study, we present an approach based on biocompatible nanocarriers containing antimicrobial cations and known antibiotics. The matrices were prepared by coordinating Gaᴵᴵᴵ or Inᴵᴵᴵ to formulations of chitosan/tripolyphosphate or catechol-functionalized chitosan, with or without encapsulated antibiotics, yielding particles of 100–200 nm hydrodynamic diameters. MDR clinical isolates of P. aeruginosa were found to be effectively inhibited by the nanocarriers under nutrient-limiting conditions. Fractional inhibitory concentration (FIC) indices revealed that cation- and antibiotic-encapsulated nanomatrices were effective against both Gram-negative and Gram-positive pathogens. Metallophores, such as deferoxamine (DFO) were probed to facilitate the sequestration and transport of the antimicrobial cations Gaᴵᴵᴵ or Inᴵᴵᴵ. Although the antimicrobial activities were less significant with DFO, the eradication of biofilm-associated bacteria showed promising trends against P. aeruginosa and S. epidermidis. Interestingly, indium-containing compounds showed enhanced activity on biofilm formation and eradication, neutralizing P. aeruginosa under Fe-limiting conditions. In particular, Inᴵᴵᴵ-crosslinked catechol-modified chitosan matrices were able to inhibit pathogenic growth together with DFO. The nanocarriers showed low cytotoxicity towards A549 cells and improvable CC₅₀-values with NIH/3T3 cells.