The combined action of Ag-NPs and kanamycin leads to a synergistic increase in bacterial activity. TEM analysis showed that sublethal concentrations of Ag-NPs (6–7 μg mL⁻¹) altered the bacterial membrane potential and caused ultrastructural damage, thus increasing the cell membrane permeability. There were no chemical interactions between Ag-NPs and antibiotic drug molecules detected [80].

The antibacterial efficiency of ampicillin, kanamycin, erythromycin, and chloramphenicol against Staphylococcus aureus, Micrococcus luteus, Escherichia coli, and Salmonella typhi was increased in the presence of Ag-NPs. The authors associate a synergistic increase in antibacterial activity with the bonding reaction between antibiotic molecules and nano-silver. The antibiotic molecules, which contain hydroxyl and amido active groups, can react with Ag-NPs by chelation [81].

Ceftazidime, imipenem, meropenem, and gentamicin sulfate, in combination with Ag-NPs, were tested [82] for their antibacterial effects against three isolates of Burkholderia pseudomallei. The results showed that the combination of these antibacterial drugs with Ag-NPs restored antibiotics’ bactericidal efficiency against the bacterial strain that had been shown previously to be resistant to the antibiotics. The bacterial cells were destroyed by the antibiotic–Ag-NPs combinations.

A combination of Ag-NPs and an antibiotic (enoxacin, kanamycin, neomycin, and tetracycline) can synergistically inhibit the bacterial growth of drug-resistant Salmonella typhimurium [83]. According to UV–vis and Raman spectroscopy, these four antibiotics can form complexes with Ag-NPs, while ampicillin and penicillin do not. Therefore, no synergistic effect was observed for the latter.

Hybrid systems based on Ag-NPs with the antibacterial drugs dioxidine and gentamicin sulfate have increased antibacterial efficacy (disk diffusion method) against Staphylococcus aureus, Mycobacterium cyaneum, and Escherichia coli [84]. Their inclusion in biopolymer matrices based on gelatin, calcium alginate, and bovine serum albumin did not lead to the disappearance of the observed effect [85,86].

The combination of Ag-NPs with antibiotics such as polymyxin B or rifampicin showed synergistic antibacterial effects against carbapenem-resistant Acinetobacter baumannii. In the case of tigecycline and Ag-NPs, only an additive effect was observed [87]. In vivo with Ag-NPs, the antibiotic combinations led to better survival ratios in Acinetobacter baumannii-infected mice than those obtained with single drug treatment.

Ag-NPs (15–25 nm) in combination with antimicrobial agents, including kanamycin, colistin, rifampicin, and vancomycin, displayed synergy against both wild-type and antimicrobial-resistant Klebsiella pneumonia isolates [88].

Ag-NPs were effective against the multidrug-resistant bacterial strains Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa. A remarkable reduction in their effective concentration was observed after combination with 1/4 of the MIC of vancomycin [96].

The combination of antibiotic-inorganic NPs makes it possible to cope with microorganisms resistant to antibiotics. Silver covalently bound to cyanographene kills Ag-NPs-resistant bacteria at concentrations 30 times lower than Ag-NPs. The antibacterial activity of the system does not rely on the release of Ag-NPs or ions. Molecular dynamics simulations suggest a strong interaction of Ag-cyanographene with the bacterial membrane [97].

The combined and individual antibacterial activities of the five conventional antibiotics (imipenem, trimethoprim, gentamycin, vancomycin, and ciprofloxacin) and Ag-NPs were investigated against eight different multidrug-resistant bacterial species using the Kirby–Bauer disk-diffusion method. These multidrug-resistant bacterial strains include: Staphylococcus aureus, (resistant to trimethoprim and vancomycin); Micrococcus luteus (resistant to trimethoprim, gentamycin, and vancomycin); Enterococcus faecalis, Pseudomonas aeruginosa, and Escherichia coli (resistant to trimethoprim, vancomycin, and ciprofloxacin); Acinetobacter baumannii (resistant to imipenem, trimethoprim, gentamycin, and vancomycin); Klebsiella pneumoniae (resistant to trimethoprim). The synergistic effect of antibiotics and Ag-NPs resulted in a 0.2–7.0 (average, 2.8) fold-area increase in antibacterial activity (Kirby–Bauer disk-diffusion method) [98].

Synergistic activity of Cu-NPs with erythromycin, azithromycin, and norfloxacin was detected against Gram-positive bacteria (Staphylococcus spp.) and Gram-negative bacteria (Escherichia coli, Klebsiella spp., Shigella spp., and Pseudomonas spp.) using the standard disc diffusion method [89].

Cu-NPs with dioxidine hybrid nanocomposites showed enhanced activity compared with the total antibacterial effect of individual components [90].

A synergistic antibacterial effect against E. coli was revealed [92] for CuO-NPs combined with cephalexin. It was shown that the presence of antibiotics does not increase Cu²⁺ release, Cu²⁺ uptake, or reactive oxygen species generation. Possible mechanisms of the combined action of the antibiotic molecules and CuO-NPs include the following stages:

• Cephalexin molecules form a high concentration on CuO-NPs surface;
• Concentrated cephalexin molecules interacted more strongly with the E. coli cell walls and destroy it more effectively than individual antibiotic molecules;
• CuO-NPs cause secondary damage by inhibiting the lipids and proteins of the cell wall;
• CuO-NPs are easier to get into the cell to bind to the proteins and DNA molecules.

Cu-NPs obtained by means of the green synthesis method using green tea extract (Camellia sinensis) were studied for antibacterial activity with antibiotics against Micrococcus luteus, Streptococcus mutans, Escherichia coli, and Salmonella Typhi [91]. The synergistic activity of Cu-NPs with ampicillin, amoxicillin, gentamicin, and ciprofloxacin was evaluated by means of the disk-diffusion method. It is assumed that the reaction between the antibiotic molecules and Cu-NPs led to synergism. The antibiotic molecules containing the following active groups, such as hydroxyl and amido can easily react with the surface metal centers of Cu-NPs by chelation.

Synergism between Au-NPs and ceftriaxone against Klebsiella pneumonia had been observed [93]. An increase in the antibacterial efficacy of Au-NPs with antibiotics in comparison with antibiotics alone has been established for Au-NPs and gentamicin against Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. This increase was also found for Au-NPs with clindamycin against Enterococcus faecalis, Au-NPs with bacitracin against Staphylococcus epidermidis, and Au-NPs and polymyxin B against Staphylococcus saprophyticus.

Mixture of Au-NPs and cefotaxime demonstrated a synergistic increase in antibacterial activity against Salmonella typhi, Salmonella typhimurium, and Salmonella enteritidis. However, the combination of Au-NPs with kanamycin exhibited no interaction [94]. The discovered synergism of Au-NPs and antibiotics is associated with the influence of components on the integrity of the membrane.

ZnO-NPs conjugated to ciprofloxacin show synergistic antibacterial activity against multiple bacterial pathogens (Streptococcus spp., Bacillus subtilis, Klebsiella spp., and Escherichia coli). There was a 2.9-fold increase in the antibacterial activity of NPs-ciprofloxacin conjugates against E.coli and a 2.8-fold increase for Streptococcus spp. as compared to ciprofloxacin alone [95].

ZnO-NPs conjugated with clinically approved drugs (quercetin, ceftriaxone, ampicillin, naringin, and amphotericin B) were studied for their activity against several gram-positive (methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes) and gram-negative (Escherichia coli K1, Serratia marcescens, and Pseudomonas aeruginosa) bacteria. Drug alone and drug-NPs comparisons showed that the NPs exceptionally increased the antibacterial potency of the drugs. Conversely, ZnO-NPs and drug-conjugated NPs showed negligible cytotoxicity against human cell lines except amphotericin B (57% host cell death) and amphotericin B-conjugated with ZnO-NPs (37% host cell death) [99].

However, the joint effectiveness of ZnO-NPs and antibiotics is not always detected. The antimicrobial activity of ZnO-NPs was assessed against pathogenic bacteria (Escherichia coli) and fungi (Aspergillus niger). However, in combination with the antibiotic penicillin, there was a decrease in the antimicrobial activity against bacteria and fungi as compared to antibiotics. A possible reason for the decrease in the effectiveness of Zn-O NPs and antibacterial drugs is associated with the use of Aloe vera extract for the synthesis of NPs. The presence of this extract may reduce the effectiveness of the interaction of the antibacterial drug with both ZnO-NPs and bacterial cells [100].

Gram-positive and gram-negative bacterial strains’ susceptibility to ZnO-NPs is increasing after the addition of antibiotics. The effect was revealed using the standard microdilution method. Synergistic effects were found for ZnO-NPs with ciprofloxacin, ampicillin, fluconazole, and amphotericin B [101]. Experimental results also demonstrated that doping ZnO-NPs with Fe, Cu, Mn, and Co increases their antibacterial activity, including when used together with antibiotics.

Nanosize TiO₂ has the enhancement effect on the antibacterial activity of different antibiotics against methicillin-resistant Staphylococcus aureus [75]. TiO₂-NPs and amoxicillin combination has a synergic effect on Staphylococcus aureus and Escherichia coli growth, as measured by the well diffusion method [102].

Another possible mechanism of action of hybrid nanosystems is based on antibiotics and metal NPs formation of active antibacterial complexes of metal ions and antibacterial drugs. Indeed, such complexes are characterized by increased antibacterial activity and effectiveness against strains resistant to antibiotics [105,106,107]. The formation of the complexes is associated with electron-donor interactions and is due to the presence of nitrogen and oxygen atoms in the chemical structure of drug molecules. For such complexes, it is possible to change the mechanism of action on the bacterial cell compared to the original antibacterial drug.

Both metal ions released from the surface of nanoparticles into the solution and surface atoms (ions) of NPs can participate in the formation of these complexes. In this case, an increase in antibacterial activity is likely with a decrease in the size and an increase in the proportion of surface atoms of inorganic nanoparticles. Also, for particles with a size of less than 10 nm, wrapping mechanisms of penetration into the bacteria are proposed. Such a metal NP could also capture antibiotic molecules.