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The opportunistic pathogen Pseudomonas aeruginosa develops increasing resistance toward even the most potent antibiotics. Like other bacteria, the pathogen produces a number of virulence factors including metallophores, which constitute an important group. Pseudomonads produce the iron-chelating metallophore (siderophore) pyochelin, which, in addition to its iron-scavenging ability, is an effector for the transcriptional regulator PchR in its Fe III -bound form (ferripyochelin). In the present study, docking studies predicted a major ferripyochelin binding site in PchR, which prompted the exploration of nor-pyochelin analogues to produce tight binding to PchR, and thereby upregulation of the pyochelin metabolism. In addition, we investigated the effects of using the analogues to bind the antimicrobial cations Ga III and In III . Selected analogues of nor-pyochelin were synthesized, and their Ga III - and In III -based complexes were assessed for antimicrobial activity. The results indicate that the Ga III complexes inhibit the pathogens under iron-limited conditions, while the In III -based systems are more effective in iron-rich media. Several of the Ga III complexes were shown to be highly effective against a multidrug-resistant P. aeruginosa clinical isolate, with minimum inhibitory concentrations (MICs) of ≤1 μg/mL. Similarly, two of the In III -based systems were particularly effective against the isolate, with an MIC of 8 μg/mL. These results show high promise in comparison with other, traditionally potent antibiotics, as the compounds generally indicated low cytotoxicity toward mammalian cells. Preliminary mechanistic investigations using pseudomonal transposon mutants suggested that the inhibitory effects of the In III -based systems could be due to acute iron deficiency as a result of In III -bound bacterioferritin.

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 Ga III or In III to formulations of chitosan/tripolyphosphate or catechol-functionalized chitosan with or without encapsulated antibiotics, yielding particles of 100-200 nm in hydrodynamic diameter. MDR clinical isolates of Pseudomonas 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 Ga III or In III . Although the antimicrobial activities were less significant with DFO, the eradication of biofilm-associated bacteria showed promising trends against P. aeruginosa and Staphylococcus epidermidis . Interestingly, indium-containing compounds showed enhanced activity on biofilm formation and eradication, neutralizing P. aeruginosa under Fe-limiting conditions. In particular, In III -cross-linked catechol-modified chitosan matrices were able to inhibit pathogenic growth together with DFO. The nanocarriers showed low cytotoxicity toward A549 cells and improvable CC 50 values with NIH/3T3 cells.

The excellent physical and chemical properties of graphene make it an attractive nanomaterial and a component in high-performance nanocomposite materials. To prepare graphene-based nanocomposite materials, chemical functionalization is often necessary. Water-soluble ligands such as carbohydrates not only make the functionalized graphene compatible with aqueous media, but also introduce biorecognition, which is important for graphene to be used in biotechnology. In this study, we report the derivatization of few-layer graphene (FLG) with carbohydrates through microwave-assisted reaction of perfluorophenyl azide (PFPA). FLG was first treated with PFPA under microwave radiation. Subsequent conjugation with glycosyl amine gave carbohydrate-presenting FLG. Thermogravimetric analysis showed that microwave radiation gave a higher degree of functionalization compared to conventional heating, with higher weight losses for both PFPA and Man ligands. The carbohydrates (mannose and galactose) retained their bioactivity, as demonstrated by the lectin binding assays. Higher degree of binding toward lectins was obtained for the carbohydrate-functionalized FLG prepared by microwave radiation than the conventional heating.