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The clinical infections by Staphylococcus aureus caused an increase in morbidity and mortality rates and treatment costs, aggravated by the emergence of drug-resistant strains. Different nanotechnology-enabled approaches are being investigated that can improve the paradigm of therapeutics against S. aureus pathogenesis and infections. Nanomaterials provide a suitable platform to address this challenge, with the potential to control biofilm formation, intracellular parasitism and multidrug resistance where conventional therapies show limited efficacy. Herein, the large diversity of nanoparticles and their applications to combat S. aureus pathogenesis, including in combination with antibiotics and phytochemicals, is presented and their specific biological actions are highlighted.
The emergence of drug-resistant pathogens equipped with active defense mechanisms against different classes of antibiotics has become a global threat to human health. Conventional antibiotics belonging to various classes usually act upon bacterial pathogens by interrupting the biosynthesis of genetic materials, such as DNA, RNA and protein, cell wall/membranes, and other cellular components essential for the basic physiology of the bacteria [1]. This traditional approach has been challenged under certain conditions when the pathogens mount resistance mechanism(s) through the expression of antibiotic resistance genes, mutation of drug targets, biofilm formation, and other protective mechanisms.
Reducing or Capping Agent/Encapsulated Drug | Properties of the NPs | Biological Activities | Reference(s) |
---|---|---|---|
Gold NPs (GNPs) | |||
Padina tetrastromatica-mediated synthesis of GNPs | M: Green synthesis AS: 1–20 nm S: Spherical PDI: ~23 nm |
GNPs showed an MIC of 25 µg/mL Higher concentrations of GNPs also exhibited biofilm-eradicating ability |
[78] |
Polypeptide polymer-conjugated GNPs | M: Chemical reduction method S: Spherical AS: 23 nm AZP: 24 mV |
Polypeptide-conjugated GNPs exhibited potent antibacterial activities against clinical isolates of MDR Gram-positive bacteria, such as MRSA Excellent in vitro and in vivo biocompatibility Studies with the antioxidant N-acetyl-L-cysteine suggested that oxidative stress is responsible for the antibacterial activity of these GNPs |
[79] |
Caffeine-loaded GNPs | S: Spherical AS: 77.9 nm |
MIC was 512 µg/mL Biofilm inhibitory and biofilm eradication concentrations of 256 and 512 µg/mL, respectively GNPs eradicated persister cells of S. aureus |
[26] |
Silver NPs (SNPs) | |||
Desertifilum sp.-mediated synthesis of SNPs | M: Green synthesis S: Spherical AS: 4.5–26 nm |
Comparing the growth inhibitory activity against different pathogens, MRSA was more susceptible to the SNPs (MIC 1.2 mg/mL) Anti-staphylococcal activity of SNPs was related to ROS-induced oxidative stress |
[80] |
SNPs | M: Microwave technique S: Spherical AS: 1-3 nm AZP: Positively charged |
Interaction between SNPs and bacterial cell wall caused leakage of cytoplasmic material MIC of SNPs was 12.5 ppm against S. aureus Eradication of mixed species biofilms (Candida albicans and S. aureus) in a dose-dependent manner, with 0.53 ppm as the IC50 value SNP-functionalized catheter material was less prone to mixed species biofilm formation |
[81][82] |
Commercial SNPs | AS: 10 nm | Photolysis of staphyloxanthin via blue light increased the anti-staphylococcal activity of SNPs Blue light reduced the MIC of SNPs from 10 µg/mL to 1 µg/mL, which is safer for mammalian cells Photolysis of staphyloxanthin increased the uptake of SNPs into the bacterial cells |
[83] |
Piper longum mediated-synthesis of SNPs | M: Green synthesis S: Spherical AS: 10–40 nm |
SNPs were active against Bacillus cereus, S. aureus, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, P. aeruginosa, and Salmonella typhi SNPs were active after three months of storage |
[84] |
Gardenia thailandica leaf extract-mediated synthesis of SNPs | M: Green synthesis S: Spherical AS: 11.02–17.92 nm AZP: −6.54 ± 0.6mV |
MIC of the SNPs against S. aureus ranged from 4 to 64 µg/mL SNP at 4 × MIC and 8 × MIC eradicated the S. aureus cells at 2 h and 1 h, respectively SNPs decreased the expression of efflux pump genes norA, norB, and norC |
[85] |
Copper (CuNPs) and copper oxide NPs (CuONPs) | |||
Curcuma longa or Zingiber officinale extract-mediated synthesis of CuNPs | M: Green synthesis S: Spherical AS: 20–100 nm |
Agar well diffusion assay showed the antibacterial effect of CuNPs (1 and 5 mM) produced with C. longa was higher than those produced with Z. officinale | [38] |
TH4+/CuNPs Virkon S/CuNPs Tek-Trol/CuNPs Peracetic/CuNPs DC&R/CuNPs |
AS: The ranges of particle size were 79.88–100.62 nm (TH4+), 77.74–116.49 nm (Virkon S), 82.32–115.91nm (Tek-Trol), 90.25–105.07 nm (Peracetic), and 115.15–144.86 nm (DC&R) AZP: 2.92 and 3.43 mV |
The ability of disinfectant-loaded CuNPs to eliminate the viable bacterial colonies in biofilm surfaces was studied with different concentrations and time points At a contact time of 5 min TH4+/CuNPs (1%), Tek-Trol/CuNPs (1%), DC&R/CuNPs (16%), 10 min Peracetic/CuNPs (0.5%), or 20 min Virkon S/CuNPs (2%), significantly reduced the total viable count of S. aureus |
[39] |
CuNPs and CuONPs | M: Plasma arc discharge method AS: 78 nm (CuNPs) and 67 nm (CuONPs) |
Tested against different bacteria, CuNPs and CuONPs showed the highest zone of inhibition against S. aureus NPs induced ROS production, protein denaturation, DNA damage, and cell death |
[58] |
CuNPs | AS: 25 nm | CuNPs showed significant anti-staphylococcal activity with reduced toxicity against fibroblasts (at 6.25 µg/mL concentration) In vivo studies using S. aureus-induced mastitis rat model indicated that CuNPs improved clinical signs faster (three days) than gentamycin (four days) CuNPs reversed the S. aureus-induced histopathological changes in the mammary gland and, on the 5th day after treatment, bacterial load, mammary gland weight, and oxidative stress parameters were lower compared to the disease control and antibiotic-treated animals |
[86] |
Other metallic NPs | |||
Lactobacillus plantarum TA4-mediated synthesis of ZnONPs | S: Oval AS: 29.7 nm |
ZnONPs were effective against S. aureus from poultry samples (disc diffusion assay) MIC and MBC values were 30 and 100 µg/mL, respectively ZnONPs inhibited biofilm formation in a dose-dependent manner The results suggested that ROS generation was the underlying antibacterial mechanism |
[87] |
Pancreatin-doped ZnONPs | M: Precipitation method S: Hexagonal AS: 85 nm |
Antibacterial and virulence inhibitory activity against MRSA Protein leakage and generation of ROS were possible antibacterial mechanisms Pancreatin-doped ZnONPs sensitized the cells to vancomycin |
[88] |
Rhamnolipid-coated ZnONPs | AS: From 40 to 55 nm S: Spherical |
NPs at 0.5 mg/mL had low toxicity to fibroblast cells and low hemolytic activity NPs treatment reduced the bacterial burden in infected wound in rats, revealing a rapid wound healing within five days compared to the rhamnolipid- and clindamycin-treated wounds In histopathological analysis, the NP-treated animals showed rapid remodeling of the epidermis and the presence of ample amounts of dermal cells on the 5th day of treatment |
[89][90] |
Aspergillus terreus S1 mediated-synthesis of MgONPs | M: Green synthesis S: Spherical AS: 8–38 nm PDI: 0.2 |
Growth inhibitory activity (MIC 200 μg/mL) against B. subtilis (13.3 ± 1.9 mm, inhibition zone), E. coli (11.3 ± 0.6 mm), C. albicans (12.8 ± 0.3 mm), P. aeruginosa (14.7 ± 1.9 mm), and S. aureus (11.3 ± 0.6 mm) | [91] |
Carum copticum extract-mediated synthesis of TiONPs | M: Green synthesis S: Spherical or spheroid shaped AS: ~12 nm |
Inhibition of EPS secretion and rupture of preformed biofilms of S. aureus | [92] |
Ochradenus arabicus leaf extract-mediated synthesis of TiONPs | M: Green synthesis AS: 26.48 nm |
MIC of the TiONPs was 32 µg/mL TiONPs at 0.5 × MIC inhibited biofilm formation and EPS production by MRSA to approx. 50% MRSA strains increased production of ROS upon treatment with the TiONPs |
[93] |
Mesoporous Silica NPs (MSNs) | |||
Enzyme-functionalized MSN | M: Stober method S: Spherical AS: Lys@MSN (38 ± 5 nm), Ser@MSN (31 ± 7 nm), and DN@MSN (35 ± 4 nm) AZP: Lys@MSN (+12 ± 5 mV), Ser@MSN (−22 ± 5 mV), and DN@MSN (+27 ± 5 mV) |
Enzymes lysostaphin (Lys@MSN), serrapeptase (Ser@MSN), and DNase I (DN@MSN) were immobilized in MSNs Lys@MSNs targeted MRSA and MSSA growth by inducing cell lysis The other two enzymes immobilized in MSNs targeted the biofilm formation of S. aureus by hampering the production of proteins and eDNA Lys@MSNs showed a 7.5- and 5-fold decrease in MIC and MBIC values compared to free lysostaphin |
[94] |
Rifampicin-loaded MSN | M: Solvent extraction (e) and calcination (c) methods AS: 40 nm (c & e), 80 nm (c) AZP: 15 (40e), 13 (40c), and 14 mV (80c) DL: 29 (40e), 33 (40c), and 38% (80c) |
Hydrophilic e-MSN particles (prepared using solvent extraction) demonstrated a > 2-fold increase in Caco-2 cell uptake MSNs were efficacious against small colony variant S. aureus hosted within Caco-2 cells Compared to free rifampicin, the MSNs loaded with rifampicin reduced the level of S. aureus in Caco-2 cells 2.5-fold |
[62] |
Moxifloxacin/rifampicin-loaded MSN (gelatine/colistin coated) | M: Stober method AS: 396 nm AZP: -29.2 ± 0.65 mV |
Antibiotic-loaded MSNs were studied against MRSA osteomyelitis both in vitro and in vivo MIC of the moxifloxacin and rifampicin MSNs were 3.906 and 0.977 µg/mL, respectively Intraosseous injection of MSNs decorated with aspartic acid hexapeptide (D6, affinity towards bone tissue) reduced S. aureus load to 92% in infected rabbit femurs within 24 h MSNs showed no toxicity towards osteoblasts and macrophages in vitro, but some effects on osteoclasts over time (72 h) NPs reduced biofilm formation and the expression of the proteases staphopain, SplF, and V8 protease, whereas they increased the expression of aureolysin and the transcriptional regulator protein Rot |
[95] |
Vancomycin-loaded MSN | M: Impregnation approach S: Spherical AS: 100 nm AZP: +26.5 mV |
Antibiotic-loaded MSNs targeting bone and MRSA presented an MIC of 16 µg/mL Compared to treatment with free vancomycin, the targeted MSNs improved the recovery from orthopedic implant-related infections with MRSA in rats Hemolytic and studies with bone marrow mesenchymal stem cells indicated the biocompatibility of the MSNs, and no abnormalities were observed in the heart, spleen, liver, lung, or kidneys of treated rats |
[96] |
Quantum dots (QDs) and Carbon nanodots (CND) | |||
p-Coumaric acid QDs | M: Wet milling approach AS: 8.9 ± 3.7 nm AZP: −3.73 mV |
Antimicrobial activity against a wide spectrum of foodborne microorganisms At minimal lethal concentration (250 µg/mL), 99.9% killing of bacterial cells was observed throughout the experiment time |
[97] |
Carbon QDs from gentamycin sulfate | M: Calcination method (180 °C optimal temperature) S: Spherical AS: 2–8 nm AZP: 10.9 mV |
QDs effectively cleared bacterial pathogens like E. coli and S. aureus (MIC was 1.59 and 50.8 ng/mL at pH 5.5 and 7.4, respectively) QDs at 80 µg/mL eradicated (90%) preformed biofilms, whereas the gentamycin sulfate at the same concentration reduced only 10% of the biofilms QDs showed a low toxic profile against mammalian 3T3 cells, even at 2 mg/mL concentration |
[98] |
Carbon dots from m-aminophenol and tartaric acid | M: Hydrothermal method S: Spherical AS: 5–9 nm AZP: +33.2 ± 0.99 mV |
The positively charged carbon dots showed anti-staphylococcal activity and low toxicity toward HeLa cells The carbon dots were selectively absorbed on the cell surface through electrostatic interactions |
[99] |
Carbon dots from levofloxacin hydrochloride | S: Spherical AS: 1.25 nm |
MIC of the carbon dots against S. aureus was 128 µg/mL Mechanisms of electrostatic interaction for surface adherence and bacterial cell wall disruption were implicated in the antibacterial action No cytotoxicity was observed towards 293T cells (viability greater than 80% at a concentration of 100 μg/mL) |
[100] |
Negatively charged CNDs | M: Microwave-assisted synthesis AS: 2.5 nm AZP: −11.06 mV |
Inhibitory activity against MRSA and vancomycin-intermediate S. aureus (MIC of 630 μg/mL) | [101] |
CNDs from curcumin and citric acid | M: Hydrothermal method AZD: −15.1 mV |
CNDs showed a broad range of antimicrobial and antibiofilm activity Bactericidal efficiency was maximal at 375 μg/mL against S. aureus, E. coli, P. aeruginosa, and B. subtilis |
[77] |
Reducing or Capping Agent/ Encapsulated Drug |
Properties of the NPs | Biological Activities | Reference |
---|---|---|---|
Liposomes | |||
Lecithin and Tween-80 liposomes with Laurus nobilis leaf extract | M: Ultrasound AS: 99.05 ± 2.98 nm EE: 73.76 ± 1.10% |
MIC and MBC of plant extracts were between 100 and 500 ppm At 1500 ppm, the loaded liposomes inhibited oxidation, bacterial growth, and spoilage of minced beef inoculated with E. coli and S. aureus |
[166] |
Lecithin liposomes with co-encapsulated berberine and curcumin | M: Film hydration AS: 253 ± 22 nm AZP: −57 ± 4 mV EE: 57 ± 3% |
MIC of free berberine and curcumin were 62 and 250 µg/mL, respectively Encapsulation reduced the MIC of the drugs by approximately half and more efficiently prevented MRSA biofilm formation Free berberine and curcumin combinations showed an MIC of 31/16 µg/mL with an FIC index of 0.56 (no interaction), while the dual drug-loaded liposomes showed an MIC of 8/10 µg/mL with an FIC index of 0.13 (synergy) The liposomes were more efficient than clindamycin in reducing intracellular infection |
[167] |
Niosomes | |||
Ciprofloxacin-loaded niosomes | M: Remote-loading technique S: Spherical AS: 123 nm PDI: 0.198 EE: 79.25% |
Stable ciprofloxacin-loaded niosomes showed MIC in the range of 2–4 µg/mL against the S. aureus strains, a 4- to 5-fold increase in antibacterial potency compared to the free drug Sub-MIC inhibited the biofilm formation of ciprofloxacin-resistant S. aureus and down-regulated the icaB gene |
[122] |
Cefazolin-loaded niosomes | M: Film hydration S: Spherical AS: 100 nm AZP: −63 mV |
Cefazolin-containing niosomes removed one- to five-day-old biofilms in a concentration-dependent manner (MRSA isolates from patients with pressure sores and diabetic ulcers) Histopathological results indicated that mice treated with cefazolin-loaded niosomes recovered faster than those treated with the free drug or the untreated group |
[168] |
Quatsomes | |||
Vancomycin-loaded quatsomes from quaternary bicephalic surfactants and cholesterol | M: Sonication/dispersion method AS: 123 nm AZP: 0.169 mV EE: 52.2% |
The pH-responsive quatsomes showed 32- and 8-fold lower MICs against MRSA at pH 6 and 7.4, respectively, compared to the free vancomycin The drug-loaded quatsomes caused more significant membrane damage, had a bactericidal effect, and counteracted MRSA biofilms in vitro In a mouse skin infection model, the quatsome formulation performed better than the free antibiotic |
[125] |
Cetylpyridinium chloride (CPC)-quatsomes | ND | No toxicity towards human airway epithelial (NuLi-1) cells Low concentration inhibited the planktonic and biofilm cells of S. aureus and P. aeruginosa |
[126] |
Micelles | |||
Platensimycin-loaded micelles constructed using [poly(lactic-co-glycolic acid)-poly(2-ethyl-2-oxazoline) (PLGA−PEOz)] and PLGA-poly(ethylene glycol) (PLGA-PEG) | AS: 183 nm (PLGA−PEOz), 195 nm (PLGA-PEG) AZP: -5.37 (PLGA−PEOz), −5.42 (PLGA-PEG) EE: 41.7% (PLGA−PEOz), 40.4% (PLGA-PEG) |
Improved results against intracellular MRSA in a macrophage infection model Compared to the free drug, drug-loaded micelles showed higher potential against MRSA-induced peritonitis in mice (dose 20 mg/kg, increased survival and reduced colonization) The drug-loaded micelles were not toxic to the cells nor the animals Cmax after i.p. injection of the free drug was 28 ± 9 μg/mL, but concentrations greater than 50 μg/mL were measured after administering the encapsulated drug |
[130] |
Solid Lipid NPs (SLNs) | |||
Curcumin-loaded SLNs | M: Microemulsion method S: Spherical AS: 126.87 ± 0.94 nm PDI: 0.21 ZP: 30 ± 0.3 mV EE: 99.96% DL: 1.8% |
Curcumin SLNs were effective against pathogens such as S. aureus and E. coli Lower MIC value (142 μg/mL) than free curcumin (1000 μg/mL) The curcumin SLNs reduced the pathogens’ cell counts in contaminated food for eight days |
[169] |
Anacardic acid encapsulated in SLNs | M: Hot homogenization S: Spherical AS: 203.6 ± 3.05 nm PDI: 0.277 ± 0.02 ZP: −21.4 ± 2.81 mV DL: 76.4 ± 1.9% |
Stable for 90 days and non-toxic to the human keratinocyte cell line HaCat High anti-staphylococcal and biofilm inhibitory activities |
[134] |
Polymeric NPs | |||
Rifampicin-loaded poly-lactic acid NPs | M: Nanoprecipitation S: Spherical AS: 144 nm PDI: 0.08 AZP: −56 ± 5 mV DL: 2.2% EE: 90.5% |
NPs coated with poly-lysine were more active against the growth and biofilms of S. aureus, presumably due to enhanced interaction and slow penetration into S. aureus biofilms | [170] |
Citrus reticulata essential oil loaded in chitosan NPs | AS: 131–162 nm EE: 67.32%–82.35% AZP: 30 mV |
The loaded NPs disturbed bacterial cell membranes and displayed high anti-staphylococcal activity, as well as inhibition of biofilm formation and premature biofilms of S. aureus | [171] |
Chitosan functionalized SNP by Sygyzium aromaticum | M: Biogenic synthesis S: Spherical AS: 30–40 nm |
Effective against MRSA and VRSA Lethal toxicity towards HeLa cells and brine shrimp was observed at 325 μg/mL, which is three times higher than the effective concentration showing anticoagulation, antiplatelet, and thrombolytic activities |
[172] |
Dendrimers | |||
Platensimycin-loaded PLGA and PAMAM dendrimer NPs | M: Emulsification-evaporation AS: 175.6 nm (PLGA) and 218.1 nm (PAMAM) PDI: 0.10 (PLGA) and 0.17 (PAMAM) AZP: −17.7 mV (PLGA) and 17.2 mV (PAMAM) DL: 7.81% (PLGA) and 8.42% (PAMAM) EE: 62.1% (PLGA) and 63.2% (PAMAM) |
Inhibited MRSA growth and biofilms and killed the bacteria in a macrophage cell model more efficiently than the free drug Treatment with both types of drug-loaded NPs was effective against MRSA peritoneal infection in the mice models, with reduction of MRSA in the blood and kidneys, and full survival for 7 days, while the animals treated with the same dose of free drug (10 mg/kg, i.p.) died in 24 h In pharmacokinetic study in rats, the NPs formulations provided a 2- to 4-fold higher AUC and extended the mean residence time of the drug (Cmax approx. 80 μg/mL) Loaded PLGA and PAMAM NPs showed no appreciable effect on RAW 264.7 cell viability at concentrations well above those providing antibacterial activity (below 100 μg/mL) |
[152] |
PAMAM dendrimers with amide-conjugated vancomycin and incorporated SNP | M: Drug-PAMAM with amide conjugation AS: Dual drug-conjugated dendrimers with 68 nm AZP: 27.5 mV |
5–7-log reduction in colony-forming units of VRSA Antimicrobial resistance induction was not detected in a susceptible strain, in contrast to using the free antibiotic Good biocompatibility with IH 3T3 fibroblasts and HUVEC cells (up to 8 µg SNP/mL) and low hemolytic effects Irrigation of infected wounds in mice with the dual-drug dendrimers cleared VRSA and reduced the accumulation of granulocytes at the wound site more efficiently than the free antibiotic or the SNP-only PAMAM dendrimers |
[154] |
Polyurea (PURE) oligoethyleneimine (OEI) dendrimers | M: Grafting oligo-(2-ethyl-oxazoline) in polyurea dendrimer, followed by acid hydrolysis AZP: cationic Mw 82,871 g/mol (PURE-G4-OEI-48) and 160,788 g/mol (PURE-G3-OEI-24) |
MIC and MBC against MRSA, MSSA, Streptococcus pneumonia, Gram-negative bacteria and Candida strains below 10 μM (lower than 1 μM in the case of MRSA) PURE-G4-OEI-48 effective against Pseudomonas aeruginosa and MRSA infections in a Galleria mellonella insect model Up to 6 μM, no toxicity was observed against human bronchial epithelial 16HBE14o- and vaginal VK2 (E6/E7) cell lines, nor an effect on the health index scores of G. mellonella Live/dead assays, SEM, and molecular dynamic simulations supported a fast-killing mechanism via membrane disruption |
[159] |