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Back to Journal »International Journal of Nanomedicine» Volume 13
Authors: Zhou Kunxiang, Li C, Chen Deming, Pan Yuhua, Tao Yifang, Qu Wen, Liu Zhiling, Wang Xinfeng, Xie Sheng
Published on November 9, 2018, the 2018 volume: 13 pages 7333-7347
Single anonymous peer review
Editor who approved for publication: Dr. Linlin Sun
Zhou Kaixiang,1 Chaoli,1 Chen Dongmei,2 Pan Yuanhu,1 Yan Fei,2 Qu Wei,2 Liu Zhenli,2 Wang Xiaofang,3 Xie Shuyu1 1MOA Animal and Poultry Product Quality and Safety Risk Assessment Laboratory, Central China Hubei Wuhan Agricultural University; 2 National Standard Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory of Veterinary Drug Residue Testing, Wuhan, Hubei; 3 Hebei Institute of Animal Husbandry and Veterinary Medicine, Baoding, Hebei Abstract: Staphylococcus aureus (S. aureus) is an important zoonotic Diseased bacteria endanger the health of humans and livestock worldwide. The characteristics of Staphylococcus aureus biofilm formation, facultative intracellular survival, and growing drug resistance pose great challenges to its application in therapy. Nanoparticles are considered to be a promising method to overcome the infection treatment problems caused by Staphylococcus aureus. In this article, the current progress and challenges of nanoparticles in the treatment of Staphylococcus aureus infections are gradually concentrated. First, the survival and infection mechanism of Staphylococcus aureus is analyzed. Secondly, it provides the treatment challenges brought by Staphylococcus aureus, and then the third step, including the ability of nanoparticles to increase the penetration and accumulation of its payload of antibiotics into cells, inhibit the formation of Staphylococcus aureus biofilm and enhance antibacterial effects The advantage of the activity against resistant strains. Finally, the challenges and future prospects of nanoparticles in the treatment of Staphylococcus aureus infections are introduced. This review will help readers realize that nanosystems can effectively combat Staphylococcus aureus infections by inhibiting biofilm formation, enhancing intracellular delivery, and improving activity against methicillin-resistant Staphylococcus aureus and microcolony variant phenotypes, and Designed to help researchers are looking for more effective nanosystems to combat Staphylococcus aureus infections. Keywords: Staphylococcus aureus, infection mechanism, drug resistance, antibiotics, nanoparticles
Infections caused by Staphylococcus aureus (S. aureus) seriously threaten human health and cause huge economic losses to farms. According to calculations, about 30% of healthy people will not show any symptoms after being colonized by Staphylococcus aureus. 1-4 Staphylococcus aureus can cause a variety of diseases, such as skin infections, abscesses, impetigo, necrotizing pneumonia, sepsis, catheter-induced endocarditis, atherosclerosis, and osteomyelitis. 5-7 Especially the opportunistic infections in hospitals are extremely serious. It is reported that approximately 20% of surgical site infections are caused by Staphylococcus aureus. 8 The highly virulent methicillin-resistant Staphylococcus aureus (MRSA) is a worrying public health threat in countries around the world. Different epidemic strains have been isolated in communities and hospitals. 5 According to reports, the treatment cost of MRSA infection is US$3,700, which is higher than the treatment cost of methicillin-sensitive Staphylococcus aureus infection. In addition, the death rate is approximately three times that of the latter. 9,10
In animal husbandry, bovine mastitis caused by Staphylococcus aureus has caused a series of economic losses such as a decline in milk production and quality, an increase in culling rate and mortality. 11,12 Staphylococcal subclinical mastitis accounts for 30%. Bovine mastitis. 13 It is reported that about 380 tons of milk are lost every year due to Staphylococcus aureus infection. 14 The presence of Staphylococcus aureus in raw milk is also a public health problem for the entire food chain. The presence of Staphylococcus aureus in the cell can build a reservoir from which reinfection occurs15,16, which then leads to long-term and repeated infections. 17,18 The intracellular survival strategy of Staphylococcus aureus is associated with subclinical and recurrent infections in bovine mastitis.
The facultative intracellular parasites and biofilms of Staphylococcus aureus protect them from the host's immune response and antibiotics, 19 thus posing a huge therapeutic challenge to the global medical community. In addition, the increase in resistance of Staphylococcus aureus also makes treatment difficult. For decades, it has been reported that nanoparticle carriers have improved the permeability of their payload drugs across cell membranes, enhanced intracellular accumulation, increased the antimicrobial activity of antimicrobial agents against drug-resistant strains, provided multiple bactericidal mechanisms and potential measures to inhibit biofilms. one. The formation of Staphylococcus aureus. We used relevant keywords (nano, intracellular infection, intracellular delivery, Staphylococcus aureus strategy, nanogel) to search PubMed, Scopus, Web of Science and Cochrane Central related publications about nanoparticles in the treatment of cells Application in infection. Approximately 3,625 records and 513 closely related papers were screened for appropriate research. This article summarizes the progress, challenges and prospects of nanomedicine in the treatment of Staphylococcus aureus infection based on related publications, in order to explore more effective nanosystems to help humans win the war against Staphylococcus aureus in the future.
Invasion strategy of Staphylococcus aureus
Staphylococcus aureus is a typical facultative intracellular bacteria. In the early stage of invasion, it first adheres to the skin, nasal cavity and other body surfaces with the help of secreted factors. 20 The host adhesion process is a key step in the pathogenesis of Staphylococcus aureus. 21, 22 Staphylococcus aureus can secrete a variety of factors (Table 1) to resist the host's immune response and successfully colonize. 23,24 Among them, fibronectin binding protein A (Fnbp A), Fnbp B and wall teichoic acid promote colonization. During these processes, Staphylococcus aureus secretes some factors to help resist the host's immune defenses. For example, iron-regulated surface determinant A (Isd A) can enhance the hydrophobicity of bacterial cells, thereby helping Staphylococcus aureus resist bactericidal fatty acids.
Table 1 The function of each factor of Staphylococcus aureus is abbreviated as: Fnbp, fibronectin binding protein; Isd, iron-regulated surface determinant.
With the help of various factors, after the host adheres and colonizes, Staphylococcus aureus invades the cell and begins to survive in the cell. Bacteria can use some intelligent mechanisms to enter cells and reside in special compartments, making it difficult for the host immune system and antibacterial agents to clean them. Staphylococcus aureus survives and proliferates in cells by preventing the combination of phagosomes and lysosomes, subverting autophagy and so on. 25 Staphylococcus aureus toxin factors play a key role in the process of penetrating cell membranes and cell membranes (Table 2). 26 According to reports, β-toxin and δ-toxin are related to the penetration of cell membranes. β-toxin can hydrolyze the sphingomyelin constituting the membrane into hydrophilic phosphocholine and hydrophobic ceramide. 27 When sphingomyelin is hydrolyzed by β-toxin, the δ-toxin will accumulate in the hydrophobic ceramide domain, and the bacteria will eventually penetrate the cell membrane (Figure 1). 28 According to reports, α-toxin is a pore-forming toxin that can penetrate the host cell membrane and subsequently cause osmotic swelling, rupture, lysis, and cell death. 29,30
Table 2 Effect of Staphylococcus aureus toxin factors on intracellular survival Abbreviation: PSMα, phenol soluble modulus α.
Figure 1 Schematic diagram of Staphylococcus aureus permeabilizing cell membranes by β-toxin and δ-toxin.
After some bacteria undergo endocytosis, they can inhibit the fusion of phagosomes with lysosomes or escape from phagosomes through certain factors and mechanisms (Figure 2). Grosz et al. demonstrated that Staphylococcus aureus 6850, MW2 and LAC can escape from the phagosome of phagocytes through the mediation of phenol-soluble regulatory protein alpha (PSMα). 31 After cell invasion, the intracellular niche serves as a reservoir for survival, and chronic and repeated infections may form a chronic carrier of Staphylococcus aureus. 32
Figure 2 The mechanism of Staphylococcus aureus infecting cells. Abbreviation: SCV, small colony variant.
After successful infection, a small colony variant (SCV) of Staphylococcus aureus will be formulated. 33 There is a highly dynamic population between SCV and the normal phenotype. Tuchscherr et al. reported that 25% of Staphylococcus aureus will convert to SCV without any selective pressure. 35 Under selective environmental pressure, Staphylococcus aureus is easily converted to SCV. It can be induced by triclosan, cold stress, and high hydrostatic force. According to reports, SCVs are produced by Staphylococcus aureus in vitro culture of antibacterial drugs. 34 SCVs are related to drug resistance, reinfection and chronic infection of Staphylococcus aureus. 36-38 SCVs are difficult to detect. Compared with the normal phenotype, the host's innate immune system reduces the secretion of toxins and pro-inflammatory factors. 39 According to reports, WCH-SK2 wild-type intracellular infection promotes the expression of more factors (TLR2, tissue remodeling factors, and pro-inflammatory factors). Cytokine) than WCH-SK2SCV (only TLR2 expression is up-regulated). 40 In addition, due to the obstacles of tricarboxylic acid metabolism and energy production, the metabolic level and growth of SCV will be slower than the normal phenotype, 41-44 because of dependence on heme, menadione and thymidine. 1,45
Treatment challenges for Staphylococcus aureus infections
As mentioned earlier, Staphylococcus aureus can escape the cleansing of the innate immune system and antibacterial drugs with the help of various factors. α-toxin, β-toxin, δ-toxin, PSMα, etc. contribute to the proliferation and spread of Staphylococcus aureus in the cell and maintain its intracellular lifestyle. Several factors contribute to the formation of biofilms, which help to escape the pressure of antimicrobial agents and immunity. In addition, the SCV phenotype is one of the difficulties we encountered in the treatment of Staphylococcus aureus infection, because of its low level of metabolism and lower expression of virulence factors than the normal phenotype. A large number of antibiotics lack the ability to penetrate cell membranes and bacterial biofilms, and their residence time in cells is short, resulting in insufficient intracellular distribution and low intracellular concentration. These make the treatment of Staphylococcus aureus infection extremely challenging.
As we all know, the formation of biofilm is a quorum sensing (QS) process. When bacteria multiply, small molecular signals called autoinducers (AI) will be secreted and accumulated in the extracellular medium. When enough bacteria are reached, AI will enable a single bacteria to perceive other bacteria around it and form a biofilm. 46 Compared with planktonic Staphylococcus aureus, the biofilm formed shows higher virulence and resistance. Oyama et al. reported that the thick biofilm of Staphylococcus aureus is more virulent than the thin biofilm on the liver of mice. In addition, the biofilm helps the intracellular survival of Staphylococcus aureus, leading to chronic infections. 47 It is well known that most drugs have poor permeability to biofilms, and their activity against Staphylococcus aureus that forms biofilms is lower than that of planktonic Staphylococcus aureus. . Staphylococcus aureus. At present, Staphylococcus aureus biofilm is a serious problem, and there is no effective treatment method.
One of the main challenges in the treatment of intracellular Staphylococcus aureus infection is how to deliver enough antibacterial drugs to the site where the bacteria are located in the cell. 48 Many antibiotics have low cell membrane permeability (β-lactams and aminoglycosides), 49 non-persistent retention in cells (fluoroquinolones and macrolides), insufficient intracellular distribution, and low intracellular concentration (table 3). 50,51 Therefore, the treatment of intracellular Staphylococcus aureus infection is a huge challenge for the global medical community. As mentioned earlier, Staphylococcus aureus can easily switch to the SCV phenotype, thereby reducing the level of metabolism. Many antibiotics, especially bactericidal drugs of childbearing age (penicillin, cephalosporin), are ineffective. It is well known that when the flow of electrons in the electron transport chain is impaired, the membrane potential will drop rapidly. For aminoglycosides, the absorption of bacterial cells depends on the membrane potential. SCV occurs when the electron transport chain is broken, which lowers the membrane potential, thereby limiting the uptake of aminoglycosides (such as gentamicin). 52 In addition, the process of converting the wild phenotype to the SCV phenotype is usually related to a decrease in numbers. ATP,53 is necessary for drug molecules to enter the cytoplasm through active transport, macropinocytosis or phagocytosis.
Table 3 Challenges of conventional antibacterial drugs to Staphylococcus aureus infection
Increased drug resistance is another obstacle to the treatment of Staphylococcus aureus infections. Their multidrug resistance allows them to evade the pharmacological effects of antibiotics. In the early days, our understanding of resistant strains of Staphylococcus aureus is more about the resistance to β-lactam drugs, but recent reports indicate that Staphylococcus aureus has been resistant to daptomycin 54 and glycopeptides. Antibiotics (teicoplanin and vancomycin) developed resistance. Used to treat MRSA, especially serious infections. 55
Staphylococcus aureus has several main resistance mechanisms. The development of resistance genes is a key resistance mechanism. Resistance to methicillin or cephalosporin is conferred by the mecA gene and its homologous genes mec B and mec C. 56 The mecA gene encodes PBP2a or PBP2', a specific penicillin binding protein. These proteins degrade the β-lactam ring, thereby conferring the activity of penicillin, cephalosporin and methicillin. In addition, mecA can be transmitted through the mec genetic elements of the chromosome cassette of Staphylococcus aureus. 57 Another resistance strategy for Staphylococcus aureus is the efflux pump, which can actively expel antibacterial agents from the bacteria. Staphylococcus aureus biofilm is also related to drug resistance. 58 According to reports, due to reduced drug permeability, Staphylococcus aureus has increased drug resistance in the biofilm state. 59 At present, effective strategic measures including alternative treatments to reduce resistance to Staphylococcus aureus are essential.
Nanoparticles enhance the activity of antibiotics against Staphylococcus aureus
As mentioned earlier, due to the intelligent survival strategy and self-protection measures of Staphylococcus aureus, many antibiotics are ineffective in the treatment of infections caused by Staphylococcus aureus. Nanomedicine has become an emerging treatment method to overcome the barriers to the treatment of Staphylococcus aureus infections. It has the ability to inhibit the formation of biofilms, 60 to penetrate cells and biofilms, to enhance intracellular retention61 and to increase the antibacterial activity of the load. Antibacterial agents. Nanoparticles can passively gather in certain organs and infection sites due to their special characteristics such as nanometer size, surface charge and large specific surface area. The modified nanoparticles can further enhance the transmembrane performance of their payload drugs by actively realizing the receptors of host cells and bacterial cells. At present, many antibacterial agents are incorporated or combined with nanocarriers to enhance the pharmacological activity of sensitive and resistant Staphylococcus aureus in the normal phenotypic state and duration of action, and reduce the side effects of drugs (Table 4). Therefore, the nanoparticle drug delivery system proved to be an ideal weapon to overcome the challenge of Staphylococcus aureus infection that we are facing.
Table 4 Nanoparticle delivery system improves the antibacterial effect of Staphylococcus aureus infection. Examples Abbreviations: CaP, tricalcium phosphate; MRSA, methicillin-resistant Staphylococcus aureus; PLGA, poly(lactide-co-glycolide) ; SLN, solid lipid nanoparticles.
Due to the high permeability, nanoparticles can penetrate thick biofilms. Bastari et al. demonstrated that sodium nafcillin coated with calcium phosphate and poly(lactide-co-glycolide) (PLGA) nanoparticles loaded with levofloxacin can inhibit the formation of Staphylococcus aureus biofilms for 4 weeks. 62 Thomas et al. demonstrated that PLGA nanoparticles loaded with ciprofloxacin are more effective against Staphylococcus aureus biofilm than ciprofloxacin solution. 63 As mentioned earlier, tetracycline-loaded chitosan nanoparticles are more effective than free tetracycline in killing intracellular Staphylococcus aureus. 64 Bacillus natto antibacterial lipopeptide carboxymethyl-loaded chitosan nanoparticles showed a good inhibitory and scavenging effect on the formation of Staphylococcus aureus biofilm and the growth of bacteria attached to the surface. 65
It is well known that glycocalyx, the main component of bacterial biofilm, is usually anionic. 66 Some cationic nanoparticles loaded with antibacterial agents provide a new and promising method for the treatment of biofilm-forming Staphylococcus aureus infections. According to reports, compared with ceftazidime solution, cationic liposomal ceftazidime can significantly inhibit the biofilm formation of Staphylococcus aureus. 67 When the positively charged ions of the particles combine with the negatively charged groups of the bacterial membrane, the cell membrane of Staphylococcus aureus will be destroyed. This process creates holes in the cell membrane, causing the cytoplasmic contents to flow out of the cell and dissipate through the cell membrane The H+ gradient, which may cause cell death. 68,69
Some metal nanoparticles have been developed to effectively inhibit the biofilm formation of Staphylococcus aureus. For example, surface-adaptive gold nanoparticles exhibit enhanced photothermal ablation of MRSA biofilms under near-infrared light irradiation without causing damage to healthy tissues. The 70-nanometer size of ZnO enhances the antibacterial activity of its loaded antibacterial agent, reduces the formation of biofilms, and overcomes the MRSA on medical devices associated with implant-related infections. 71 Metal ions can cause the bacterial cell membrane to rupture and then internalize into the bacterial cytoplasm. After internalization, reactive oxygen species are formed, which then leads to DNA damage and cell death. According to reports, nanoparticles can effectively inhibit the formation of biofilms by inhibiting QS-regulated gene expression. 72
The therapeutic effect of antimicrobial agents on intracellular Staphylococcus aureus depends on the duration of the infected cells above the effective therapeutic level. The concentration of drugs in the cell depends on their ability to penetrate the cell membrane and their accumulation in the cell. It is well known that nanoparticles can improve the permeability and accumulation of payload drugs in cells. Due to the direct interaction between the particles and the Staphylococcus aureus in contact with them and the diffusion of the released drugs to Staphylococcus aureus, the increased cellular uptake and subsequent controlled release of antibiotics embedded/adsorbed by the nanoparticles can effectively enhance it. Antibacterial effect, thereby more effective treatment of intracellular infections. For example, PLGA nanoparticles can increase the intracellular gentamicin and improve the subcellular distribution, thereby showing a stronger antibacterial effect against Staphylococcus aureus. 73 Polymer nanoparticles with specific hydrophobic/hydrophilic chemical properties of ionic core and shell can also have a promising effect on bacteria through interactions through stronger electrostatic interactions between the hydrophobic part of the shell and the cell membrane and the opposite surface charge of the core . According to reports, modified nanoparticles with macrophage-specific ligands can increase the efficiency of phagocytosis, thereby increasing the intracellular concentration of antibacterial agents. 74 Chakraborty et al. found that vancomycin chitosan folic acid nanoparticles showed more effective performance and stronger effects on the surface of epithelial and bacterial cells. Anti-S. The effect of Staphylococcus aureus is compared with that of chitosan nanoparticles. 75
Liposomes are also considered as potential carriers for intracellular antimicrobial agents, because their phospholipid bilayer structure is like a cell membrane, which means that the phospholipid bilayer structure can easily bind to other groups, so it can be designed to respond Secreted bacterial toxins. Gupta et al. demonstrated that levofloxacin liposomes exhibit prolonged and improved anti-biofilm and antibacterial effects in the treatment of Staphylococcus aureus infections. 76 Recently, it was confirmed that chloramphenicol-loaded deoxycholic acid liposomes can increase the antibacterial effect of MRSA infected by keratinocytes, and the deformable liposomes maintain good biocompatibility. 77 According to reports, the compound in which the surface of vancomycin-loaded liposomes is bound to chitosan-modified gold nanoparticles has the ability to respond to bacterial toxins. 78 Liposomes have also been shown to enhance intracellular gentamicin and antibacterial activity against Staphylococcus aureus. 79 Ahani et al. also pointed out that polyhexamethylene biguanide chloride cationic liposomes can increase the antibacterial activity of high concentrations The agent is delivered to the infected cells and reduces cytotoxicity. 80 Bas et al. reported that the intracellular concentration of ofloxacin liposomes can be as high as 2.6 times. Free ofloxacin. 81 A study reported that enrofloxacin loaded liposomes can inhibit Staphylococcus aureus in neutrophils for 60 minutes. 82 According to reports, chitosan-modified liposomes containing α-lipoic acid and coenzyme Q10 also show strong bactericidal effects against Staphylococcus aureus. This new measure with multiple antibacterial mechanisms will become a potential method to reduce the development of resistance to Staphylococcus aureus. 83 In addition, a thermosensitive liposome loaded with antibiotics is designed for the temperature of the infection site to be higher than that of healthy tissues, which can be completely released at ≥39°C, and it is significantly more pronounced at 42°C than at 37°C. The ability to kill Staphylococcus aureus. 84
Solid lipid nanoparticles (SLNs) may be another promising drug delivery system with obvious advantages such as biodegradability, good biocompatibility and stability. Our previous work also showed that behenic acid SLN loaded with enrofloxacin can effectively increase the accumulation and storage time of enrofloxacin in cells. The cellular uptake and accumulation of the 85 payload enrofloxacin is affected by the zeta potential and diameter of the nanoparticles.
Some inorganic nanoparticles also show great potential to treat Staphylococcus aureus infections. For example, β-tricalcium phosphate nanoparticles have made great achievements in Staphylococcus aureus osteomyelitis due to the stimulation of bone regeneration by β-tricalcium phosphate. 86,87 The phagocytosis of ciprofloxacin-loaded niosomes is much greater than that of free ciprofloxacin, and shows higher antibacterial activity against intracellular Staphylococcus aureus88.
The antibacterial activity of nanoparticles depends on their stability to infected cells and reaching target subcellular sites in a predetermined manner. Nanoparticles enter cells through different pathways, including phagocytosis (zipper-like and trigger-like) and non-phagocytosis89 (Figure 3). Different transport pathways will affect cell uptake and intracellular distribution, thereby affecting the therapeutic effect. Most of the ingestion methods, namely clathrin-mediated endocytosis, trigger-like phagocytosis and macropinocytosis, mainly accumulate in late endosomes and/or final lysosomes to form endolysosomes (phagolysosomes) ), therefore internalized nanoparticles are usually stored in an acidic environment endosomes and/or lysosomes and/or phagolysosomes (phagolysosome). 90 This cross-cell approach will be used to combat Staphylococcus aureus accumulated in phagosomes/endolysosomes (endosomes/endolysosomes) and help increase the antibacterial effect of diffusible drugs on cytoplasmic Staphylococcus aureus. Gold Staphylococcus aureus or vesicles containing Staphylococcus aureus. Since the main intracellular parasitic sites of Staphylococcus aureus are phagosomes and cytoplasm, endosome/lysosomal transport may be very effective for Staphylococcus aureus. 28 In addition, lysosome or/and endosomal transport (ie CvME, zipper-like phagocytosis) may also be due to the ability to bypass lysosomes, and therefore is another way of intracellular antimicrobial delivery. Therefore, non-lysosomal transport may facilitate the intracellular delivery of antibiotics allergic to lysosomal enzymes and kill pathogens that invade in a similar way to bacteria. 91,92
Figure 3 The mechanism of intracellular transport of nanoparticles.
The transmembrane pathway and mechanism of nanoparticles depend on the size, zeta potential, surface hydrophilicity and shape of the nanoparticles. Clathrin-mediated endocytosis mainly targets nanoparticles ranging in size from 100 to 200 nm. Therefore, through clathrin-mediated endocytosis, 100-200 nm nanoparticles may have better intracellular co-localization with Staphylococcus aureus. For example, Sémiramoth et al. demonstrated that, compared with free penicillin G, penicillin G self-assembled nanoparticles with a size of 140±10 nm showed a stronger clathrin-dependent penetration into cells and showed enhanced intracellular Antibacterial activity of Staphylococcus aureus. 93 In addition, charge is also an important element that affects the absorption of nanoparticles. Negatively or positively charged nanoparticles appear to have more effective endocytosis than neutral nanoparticles. 94 The composition of the nanoparticle plays a key role in the absorption method, because it determines the surface characteristics of the nanoparticle. Generally, hydrophilicity/hydrophobicity affects opsonization and phagocytosis, thereby determining the fate of exogenous nanoparticles in the body. Surface hydrophobicity seems to be an important factor in enhancing nanoparticle absorption. Couvreur et al. showed that PEGylation of nanoparticles reduces the uptake of macrophages. 95 Recently, the control of phagocytosis through changes in the shape of nanoparticles has received increasing attention. Beningo et al. claimed that rigid polyacrylamide nanoparticles are easier to absorb than soft ones because they can stimulate the assembly of actin filaments, which are necessary for the formation and closure of phagosomes. 96
Drug resistance is one of the main obstacles to the fight against Staphylococcus aureus infection, especially MRSA. Facing the situation that the evolution of Staphylococcus aureus pathogens and the emergence of drug resistance are faster than the discovery and development of new drugs, the use of pharmaceutical technology to actively recover existing antibiotics will be a potential strategy. Recently, nanomedicine is considered as a promising measure to overcome the problem of MRSA. 97 According to reports, compared with vancomycin HCL, vancomycin HCl-SLN shows a more effective and longer lasting effect on resistant and sensitive Staphylococcus aureus. 98 The synergistic effect of liposomes on clarithromycin Compared with liposomal daptomycin and liposomal clarithromycin, nanoparticles with a mass ratio of 1:32 and daptomycin respectively showed enhanced anti-MRSA Activity and increase the survival rate of infected host cells. 99 Nanoparticles loaded with antibiotics may have high permeability to MRSA due to their small particle size. It is well known that nanoparticles themselves or through decoration have positive or negative surface charges. The surface charge facilitates the adsorption of nanoparticles on the surface of MRSA, which in turn helps to exhibit the high antibacterial activity of the antibacterial agent. In addition to antibacterial agents, carrier materials (metal ions, lipids and hydrogels) also have antibacterial activity. Multiple bactericidal mechanisms (metal ion release, oxidative stress induction, DNA or ribonucleic acid damage, cell membrane destruction) require multiple gene mutations at the same time, so it is difficult to avoid or produce bacterial resistance.
Some researchers have focused on the modification of nanoparticles to further enhance the effect of antimicrobial agents on MRSA. For example, compared with liposomes and free azithromycin, the liposomal payload azithromycin modified by Chol-suc-VQWRIRVAVIRK-NH2 (DP7-C) was shown by upregulation of anti-inflammatory cytokines and chemokines in a mouse model Higher anti-MRSA effect. 100 Nanoparticles that are sensitive to pH are significant for anti-drug resistance 101, because Staphylococcus aureus can produce acidity at the site of infection. 102 Some nanoparticle materials and nanoparticle modifications can make nanoparticles sensitive to pH. Nanoparticles will quickly release the drug in the acidic environment of the MRSA infection site, thereby achieving powerful activity. 103
Based on the different antibacterial activities of metals and the unique properties of nanoparticles, attempts are being made to use metal nanoparticles to overcome the resistance of MRSA. For example, Aurore et al. found that nano-silver exhibits excellent antibacterial activity against intracellular MRSA in osteoclasts at a non-toxic concentration level, thus showing potential measures for the treatment of bone infections. 104 There is some controversy that metal ions may increase resistance to osteoclasts. germ. In the future, the combination of existing nanoparticles and improved technology will further increase the activity of antibiotics against resistant Staphylococcus aureus and make it widely used clinically.
Improve activity against SCV phenotype
The typical feature of the SCV phenotype is that the metabolic level and growth rate are lower than the normal phenotype, which makes it difficult for Staphylococcus aureus to be detected by the immune system, and it is also difficult to be destroyed by antibacterial drugs. Some researchers are trying to enhance the activity of antibacterial agents against the SCV phenotype of Staphylococcus aureus. Richter et al. proved that protoporphyrin and deferiprone can increase the activity of antibiotics against Staphylococcus aureus SCV because of their ability to increase the level of cell metabolism. 105 Drugs that can increase cell metabolism will become a new approach to the treatment challenge. SCVs use them to modify nanoparticles.
Improve the efficiency of treatment in the body
Through the phagocytic cells of the mononuclear phagocytic system (MPS) and locally impaired lymphatic drainage, as well as increased capillary permeability due to inflammation, nanoparticles are more likely to accumulate in infection foci in the body. In these processes, nanoparticles have more opportunities to encounter Staphylococcus aureus inside and outside the cell. Many studies have shown that nanoparticles can improve the effectiveness of antibacterial agents in treating Staphylococcus aureus infections in the body. For example, due to the enhanced bioavailability and sustained-release performance, hydrogenated castor oil SLNs loaded with tilmicosin have a better therapeutic effect than free tilmicosin because of its better bioavailability and sustained-release performance. 106 Xie et al. proved that gold nanoclusters exhibit excellent therapeutic effects on MRSA-induced bacteremia models and skin infection models due to reasonable circulation time and ultra-small size of nanoclusters. 107 According to reports, the anti-MRSA activity of vancomycin pH-responsive lipid nanoparticles is 1.8 times higher than that of vancomycin in vivo. 108 In addition, some inorganic materials with good biological activity and low toxicity (vanadium dioxide)109 also show satisfactory effects on Staphylococcus aureus infection in the body. For example, silica nanoprobes coated with vancomycin and decorated with polyelectrolyte-cyclopropionate complex can selectively achieve fast (4 hours after injection) and high sensitivity (105 colony forming units) near-infrared fluorescence Imaging and realizing effective photothermal treatment of MRSA infection in mice. It is worth noting that the nanoprobe can track the changes of MRSA infection for a long time (16 days). 110 Bacterial response functional nanomaterials will provide opportunities to fight bacterial drug-resistant infections. The nanohydrogel system is also considered to be an effective medium for the challenge of Staphylococcus aureus because of its strong adhesion to the infected site, sustained drug release, reduced dosing frequency, and excellent inhibition of bacterial growth. Nimal et al. found that using a Drosophila melanogaster infection model, a chitosan gel containing tigecycline nanoparticles showed significant activity against Staphylococcus aureus. 111
Nanoparticles with antibacterial agents are used as a potential weapon against Staphylococcus aureus infection due to their specific biological properties, and they show more advantages than traditional preparations. However, the research of nanosystems against Staphylococcus aureus infection is not complete, and we still face challenges in nanosystems and reasonable scale production. Because the bacteria are in a dormant or quiescent state, there is some contradiction between the lack of enhanced activity against intracellular pathogens and the accumulation of certain antibacterial drugs in the cells through nanoparticles 112,113 and the inactivation of drugs in unfavorable environments in the cells. Compared with free rifampicin, polyisobutyl cyanoacrylate nanoparticles did not enhance the activity against mycobacteria, although the nanoparticles increased the amount of rifampicin in the cell. 114 The SCV phenotype of Staphylococcus aureus has a lower metabolic level and growth rate than the normal phenotype, so it is difficult for antimicrobial agents to kill them. Currently, almost no nanoparticles have been developed to combat the SCV phenotype of Staphylococcus aureus. In order to eliminate the persistent SCV phenotype, new methods of nanoparticle development must be established. Combination therapy, whether through the incorporation of multiple antibacterial drugs with synergistic effects, or the combined use of antibiotics and other intervention drugs with different antibacterial mechanisms, may be a promising method to combat Staphylococcus aureus quiescence or dormancy. Another major challenge we face is the premature release of nanoparticles. The key issue for successful treatment of intracellular Staphylococcus aureus with biofilm and drug resistance is the stability of the nanoparticles during transportation, that is, to ensure that the nanoparticles do not release the drug prematurely before reaching the lesion and to ensure that the drug is avoided on the way The inactivation. Unfortunately, it is difficult to achieve the ideal ability of nanoparticles to reach the target site without premature release of the drug. Another insurmountable challenge is the use of nanoparticle payloads of antimicrobial agents to combat intracellular infections located outside of MPS. It is well known that the uptake of mononuclear phagocytes is very beneficial for the treatment of MPS infection. However, Staphylococcus aureus can infect non-professional phagocytes, namely intestinal epithelial cells, hepatocytes, fibroblasts and epithelial cells. The low phagocytic capacity of these cells prevents Staphylococcus aureus in infected non-MPS tissues from being targeted. Therefore, the current antimicrobial nanoparticle system should have the ability to distinguish the health of infected cells and tissues, and have specific drug release according to the affected environment. Currently, the performance of antibacterial drugs loaded with nanoparticles is evaluated in vitro and in vivo. Due to the complexity and unpredictability of the transportation of nanoparticles in the body, the clinical efficacy of nanoparticles is still questionable, and its clinical evaluation should be strengthened.
As far as nanoparticles are concerned, they should be non-toxic, high-load, low-cost, and capable of reproducible manufacturing and verification and characterization to achieve better clinical applications. Unfortunately, current nanoparticle delivery systems rarely meet these requirements (Table 5). For example, the poor drug loading capacity and instability of liposomes are still an important issue. 41 Due to the mutual repulsion between hydrophilic active molecules and hydrophobic polymers, the drug-carrying capacity of polymer nanoparticles for polar antibacterial agents is always low. The lack of reasonable mass production is still another bottleneck for polymer nanoparticles. Although sentinel lymph nodes overcome some of the shortcomings of liposomes and polymer nanoparticles, loading capacity and premature release are still major challenges. Metal ion nanoparticles are not selective for eukaryotic cells and bacterial cells, so these nanoparticles must be effectively transported to the site of infection. 115 Other nanoparticles, namely β-tricalcium phosphate nanoparticles, are also plagued by these problems. The loading capacity and stability of nanoparticles are being improved through the modification and combination of various advantages of different nanoparticles. For example, a new type of composite drug nanocarrier that combines inorganic (hydroxyapatite) and organic nanomaterials (chitosan/konjac glucomannan) and liposome technology has a high load compared with free vancomycin Capability, sustained-release characteristics and strong activity against Staphylococcus aureus biofilms. 116 Multifunctional nanoparticle delivery systems with clear clinical efficacy, affordability and good compliance should be developed to avoid the shortcomings of current nanoparticles and have Comprehensive advantages of various nano systems.
Table 5 Abbreviations for the shortcomings of various nanoparticle drug delivery systems: β-TCP, β-tricalcium phosphate.
Facing the challenge of treating Staphylococcus aureus infections, we must discover and develop more new nanosystem methods to effectively treat Staphylococcus aureus infections. As mentioned earlier, Staphylococcus aureus can survive outside the cell and in different subcellular structures. The intracellular efficacy of nanoparticles depends not only on the release of antibacterial agents and the high levels of cell-related drugs, but also on the positioning between the drug and the intracellular bacteria. 90 At present, the focus of research is whether antibacterial agents can penetrate cell membranes into cells, but they rarely play a role in cells. Delivery and release of drugs in subcellular structures. The intracellular co-localization of different nanoparticles and Staphylococcus aureus should be enhanced by changing their physicochemical properties and appropriate modifications, so as to achieve better co-localization of the drug and Staphylococcus aureus, so as to achieve a satisfactory therapeutic effect.
As we all know, the pH of the infection site and the intracellular environment are lower than the pH of healthy tissues and the extracellular environment, respectively. pH-sensitive nanoparticles are more promising against Staphylococcus aureus infection. 117 Among various nanoparticles, nanogels are pH-dependent and may be used for targeted therapy of Staphylococcus aureus infections. At lower pH values, the drug-loaded nanogel releases faster. According to reports, nanogels are released with a small amount of payload antibacterial agent in infected breast milk with a pH value of 7.0~7.4, while at lower pH values (5.0~5.5), they are released quickly and completely where Staphylococcus aureus is located. Endosomes and lysosomes. 118,119 In addition, nanogel can adhere to the breast for a long time, because it has strong mucus adhesion, and because of its small size, it can easily penetrate into breast epithelial cells, with greater surface capacity and stronger coagulation. The bioadhesion of glue materials (such as sodium alginate, chitosan). These advantages will help transport its payload drug to infected sites and cells. Therefore, nanogels will be an effective weapon to achieve targeted therapy of Staphylococcus aureus and should attract more attention (Figure 4), especially the combination of nanogels and other nanoparticles.
Figure 4 The mechanism of nanogels releasing drugs in the breast. Abbreviations: Staphylococcus aureus, Staphylococcus aureus.
Faced with the evolution of pathogens and the emergence of drug resistance of pathogens faster than the discovery and development of new drugs, nanoparticle delivery systems with multiple bactericidal mechanisms, such as coating with antibacterial peptides and antibacterial enzymes or coupling antibacterial agents, should be 120,121 In addition, conventional antibacterial drugs or treatment measures may not be able to completely eliminate all bacteria, resulting in the persistence of bacteria after treatment. The challenges of biofilm and SCV from Staphylococcus aureus are still difficult to deal with. In the future, antimicrobial photodynamic therapy (APDT) and photon induced photoacoustic flow (PIPS) should receive more attention. According to reports, the combination of APDT and PIPS with nanoparticles may damage the functional integrity of bacterial cell walls, DNA, biofilms, and bacterial membrane proteins. 122-124 Shrestha et al. found that APDT and chitosan-coupled rose red nanoparticles (CSRBnps) achieved endotoxin inactivation and eliminated all tested inflammatory factors from macrophages. CSRBnps with APDT showed the ability to effectively inactivate endotoxins. 125
Nanoparticle-mediated antibacterial drug delivery is a complex dynamic process in vivo, including absorption, distribution, metabolism, excretion and drug release. The dynamic process affects the absorption rate and fate of the nanoparticles and their payload drugs. Therefore, in-depth study of the dynamic process of nanoparticles in cells and tissues and the invasion mechanism of Staphylococcus aureus is a prerequisite for the development of suitable nanosystems to effectively treat Staphylococcus aureus infections. In the future, we should study nanoparticles to achieve satisfactory results at the molecular, cellular, and animal levels. Smart nanoparticles for the invasion process of Staphylococcus aureus should be developed to improve the treatment effect of Staphylococcus aureus infections. According to the penetration characteristics of Staphylococcus aureus cell membranes, a red blood cell membrane coated nanogel (red red blood cell membrane coated [RBC]-nanogel) system used as a "trap" was discovered (Figure 5). 126 RBC-Nanogel When bacteria realize specific receptors on red blood cell membrane and then secrete β-toxin and δ-toxin into RBC-nanogel, it can kill Staphylococcus aureus with the loaded antibacterial agent.
Figure 5 The process of Staphylococcus aureus entering the cell membrane to coat nanoparticles. Abbreviations: Staphylococcus aureus, Staphylococcus aureus.
This work was supported by the National Natural Science Foundation of China (Grant No. 31772797).
The authors report no conflicts of interest in this work.
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