The ability of bacteria to develop resistance to antibiotics is threatening one of the pillars of modern medicine. It was recently understood that bacteria can develop resistance even to silver nanoparticles by starting to produce flagellin, a protein which induces their aggregation and deactivation. This study shows that silver covalently bound to cyanographene (GCN/Ag) kills silver‐nanoparticle‐resistant bacteria at concentrations 30 times lower than silver nanoparticles, a challenge which has been so far unmet. Tested also against multidrug resistant strains, the antibacterial activity of GCN/Ag is systematically found as potent as that of free ionic silver or 10 nm colloidal silver nanoparticles. Owing to the strong and multiple dative bonds between the nitrile groups of cyanographene and silver, as theory and experiments confirm, there is marginal silver ion leaching, even after six months of storage, and thus very high cytocompatibility to human cells. Molecular dynamics simulations suggest strong interaction of GCN/Ag with the bacterial membrane, and as corroborated by experiments, the antibacterial activity does not rely on the release of silver nanoparticles or ions. Endowed with these properties, GCN/Ag shows that rigid supports selectively and densely functionalized with potent silver‐binding ligands, such as cyanographene, may open new avenues against microbial resistance.

When combined with nanomaterials, antibiotics show antibacterial activity against susceptible and resistant bacterial strains at significantly lower concentrations. Unfortunately, to date, no research study has examined the effect of the antibiotic mode of action and mechanism of bacterial resistance on the effectiveness of combined antibacterial treatment with nanomaterials. Therefore, in this review, we performed a thorough analysis and critical evaluation of previously published data related to the combined antibacterial effect of antibiotics with nanostructured materials with a targeted focus on relationships between antibiotic’s modes of action and bacterial resistance mechanisms for relevant nanomaterials and their impact on the resulting synergistic effects. Following thorough data analysis and critical discussion, we have discovered and are the first who present that antibiotic’s mode of action and bacterial resistance mechanism determine the final effectiveness of combined antibacterial treatment with nanomaterials. We therefore conclude that only certain combinations of nanomaterials with antibiotics can lead to the enhancement and restoration of the antibacterial effectiveness of antibiotics against certain resistant bacteria. Moreover, the recently occurring development of bacterial resistance towards nanomaterials is also discussed together with a possibility of how to prevent it. All discovered findings provide a new view and perspective on this issue helping to navigate further approaches to combat the antibiotic crisis.

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The number of antibiotic-resistant bacterial strains is increasing due to the excessive and inappropriate use of antibiotics, which are therefore becoming ineffective. Here, we report an effective way of enhancing and restoring the antibacterial activity of inactive antibiotics by applying them together with a cyanographene/Ag nanohybrid, a nanomaterial that is applied for the first time for restoring the antibacterial activity of antibiotics. The cyanographene/Ag nanohybrid was synthesized by chemical reduction of a precursor material in which silver cations are coordinated on a cyanographene sheet. The antibacterial efficiency of the combined treatment was evaluated by determining fractional inhibitory concentrations (FIC) for antibiotics with different modes of action (gentamicin, ceftazidime, ciprofloxacin, and colistin) against the strains Escherichia coli, Pseudomonas aeruginosa, and Enterobacter kobei with different resistance mechanisms. Synergistic and partial synergistic effects against multiresistant strains were demonstrated for all of these antibiotics except ciprofloxacin, which exhibited an additive effect. The lowest average FICs equal to 0.29 and 0.39 were obtained for colistin against E. kobei and for gentamicin against E. coli, respectively. More importantly, we have experimentally confirmed for the first time, that interaction between the antibiotic's mode of action and the mechanism of bacterial resistance strongly influenced the combined treatment’s efficacy.