Copper-catalyzed Azide-alkyne Cycloaddition Research Articles

Solution-processable polytriazoles from spirocyclic monomers for membrane-based hydrocarbon separations.

The thermal distillation of crude oil mixtures is an energy-intensive process, accounting for nearly 1% of global energy consumption. Membrane-based separations are an appealing alternative or tandem process to distillation due to intrinsic energy efficiency advantages. We developed a family of spirocyclic polytriazoles from structurally diverse monomers for membrane applications. The resulting polymers were prepared by a convenient step-growth method using copper-catalysed azide-alkyne cycloaddition, providing very fast reaction rates, high molecular weights and solubilities in common organic solvents and non-interconnected microporosity. Fractionation of whole Arabian light crude oil and atmospheric tower bottom feeds using these materials enriched the low-boiling-point components and removed trace heteroatom and metal impurities (comparable performance with the lighter feed as the commercial polyimide, Matrimid), demonstrating opportunities to reduce the energy cost of crude oil distillation with tandem membrane processes. Membrane-based molecular separation under these demanding conditions is made possible by high thermal stability and a moderate level of dynamic chain mobility, leading to transient interconnections between micropores, as revealed by the calculations of static and swollen pore structures.

Copper phosphorylated cellulose nanofibers mediated azide-alkyne cycloaddition click reaction in water

Heterogenous copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC) was performed by using the phosphorylated carbohydrate-based cellulose nanofibers loaded with copper(II) ions. The copper-containing phosphorylated cellulose nanofibers (here after noted Cu(II)-PCNFs) were prepared in two different morphologies, namely the paper and foam ones and characterized by different techniques, including Scanning Electronic Microscopy (SEM), Energy Dispersive X-ray (EDX), Brauner-Emmett-Teller (BET), FT-IR spectroscopy (FTIR), Thermal Gravimetric Analysis (TGA), X-ray Photoelectron spectroscopy (XPS) and Atomic Force Microscopy (AFM). Cu(II)-PCNFs showed high activity in the CuAAC reaction when applied to the ligation of various organic azides and terminal alkynes without any reducing agent, resulting in the regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles in water at room temperature. These nanofibers were recovered and reused with no significant loss of catalytic activity or selectivity. A carbohydrate-based bio-support cellulose as reliable heterogenous catalyst was efficiently developed in view of taking the click chemistry concept to sustainable chemistry.

Expanding the synthesis of a library of potent glucuronic acid glycodendrons for Dengue virus inhibition

Multivalent glycodendrons are valuable tools to mimic many structural and functional features of cell-surface glycoconjugates and its focal position scaffolds represent important components to increase specificity and affinity. Previous work in our group described the preparation of a tetravalent glucuronic acid dendron that binds with good affinity to Dengue virus envelope protein (KD = 22 μM). Herein, the chemical synthesis and binding analysis of a new library of potent glucuronic acid dendrons bearing different functional group at the focal position and different level of multivalency are described. Their chemical synthesis was performed sequentially in three stages and with good yields. Namely a) the chemical synthesis of the oligo and polyalkynyl scaffolds, b) assembling with fully protected glucuronic acid-based azide units by using a microwave assisted copper-catalysed azide-alkyne cycloaddition reaction and c) sequential deprotection of hydroxyl and carboxylic acid groups.Surface Plasmon Resonance studies have demonstrated that the valency and the focal position functional group exert influence on the interaction with Dengue virus envelope protein. Molecular modelling studies were carried out in order to understand the binding observed. This work reports an efficient glycodendrons chemical synthesis that provides appropriate focal position functional group and multivalence, that offer an easy and versatile strategy to find new active compounds against Dengue virus.

Click Chemistry and Radiochemistry: An Update.

The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists to combine molecular subunits as if they were puzzle pieces. Over the last 25 years, the click chemistry toolbox has swelled from the canonical copper-catalyzed azide-alkyne cycloaddition to encompass an array of ligations, including bioorthogonal variants, such as the strain-promoted azide-alkyne cycloaddition and the inverse electron-demand Diels-Alder reaction. Without question, the rise of click chemistry has impacted all areas of chemical and biological science. Yet the unique traits of radiopharmaceutical chemistry have made it particularly fertile ground for this technology. In this update, we seek to provide a comprehensive guide to recent developments at the intersection of click chemistry and radiopharmaceutical chemistry and to illuminate several exciting trends in the field, including the use of emergent click transformations in radiosynthesis, the clinical translation of novel probes synthesized using click chemistry, and the advent of click-based in vivo pretargeting.

Click synthesis and self-assembly of novel dendritic ethylene glycol/alkyl-substituted diarylated triazoles into supramolecular nanofibers

Copper-catalyzed 1, 3-dipolar cycloaddition reaction between azides and alkynes under mild conditions has been known to exhibit high selectivity and good yields of 1, 2, 3-triazole. Additionally, 1, 2, 3-triazoles are used in various medical and pharmaceutical applications. Herein, we present novel low molecular weight organogelators from fluorescent ethylene glycol/alkyl-substituted 2, 6-diarylated pyridine 1, 2, 3-triazoles. Compact supramolecular architectures were created by the self-assembly of the synthesized gelators. The gel formation activity of the prepared ethylene glycol/alkyl-substituted 2, 6-diarylated pyridine triazoles were presented. The synthesis process was achieved by copper-catalyzed alkyne-azide cycloaddition (CuAAC) of ethylene glycol/alkyl-functionalized aromatic azide with aromatic alkyne bearing alkyl ester tails of various lengths. The ethylene glycol/alkyl-functionalized diaryl triazoles were investigated by 1H/13C NMR and FTIR spectroscopic methods. Triazoles with long ethylene glycol and/or alkyl ester tails showed an enhanced gelation activity as compared to those with shorter ethylene glycol and/or alkyl ester tails. The morphological features of the self-assembled ethylene glycol/alkyl-substituted arylated triazoles were studied by scanning electron microscopy (SEM), demonstrating supramolecular nanofibrous assemblies. Those supramolecular assemblies were forced by van der Waals and π-stacks interactions. Both antibacterial activity and cytotoxicity of the synthesized arylated triazole gelators were studied.

Synthesis of a Series of Trimeric Branched Glycoconjugates and Their Applications for Supramolecular Gels and Catalysis.

Carbohydrate-derived molecular gelators have found many practical applications as soft materials. To better understand the structure and molecular gelation relationship and further explore the applications of sugar-based gelators, we designed and synthesized eight trimeric branched sugar triazole derivatives and studied their self-assembling properties. These included glucose, glucosamine, galactose, and maltose derivatives. Interestingly, the gelation properties of these compounds exhibited correlations with the peripheral sugar structures. The maltose derivative did not form gels in the tested solvents, but all other compounds exhibited gelation properties in at least one of the solvents. Glucose derivatives showed superior performance, followed by glucosamine derivatives. They typically formed gels in toluene and alcohols; some formed gels in ethanol-water mixtures or DMSO water mixtures. The glycoclusters 9 and 10 demonstrated rate acceleration for the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. These were further studied for their metallogels formation properties, and the copper metallogels from compound 9 were successfully utilized to catalyze click reactions. These metallogels were able to form a gel column, which was effective in converting the reactants into the triazole products in multiple cycles. Moreover, the same gel column was used to transform a second click reaction using different reactants. The synthesis and characterization of these compounds and their applications for catalytic reactions were discussed.

Disrupting Protein Expression with Double-Clicked sgRNA-Cas9 Complexes: A Modular Approach to CRISPR Gene Editing.

CRISPR-Cas9 is currently the most versatile technique to perform gene editing in living organisms. In this approach, the Cas9 endonuclease is guided toward its DNA target sequence by the guide RNA (gRNA). Chemical synthesis of a functional single gRNA (sgRNA) is nontrivial because of the length of the RNA strand. Recently we demonstrated that a sgRNA can be stitched together from three smaller fragments through a copper-catalyzed azide-alkyne cycloaddition, making the process highly modular. Here we further advance this approach by leveraging this modulator platform by incorporating chemically modified nucleotides at both ends of the modular sgRNA to increase resistance against ribonucleases. Modified nucleotides consisted of a 2'-O-Me group and a phosphorothioate backbone in varying number at both the 5'- and 3'-ends of the sgRNA. It was observed that three modified nucleotides at both ends of the sgRNA significantly increased the success of Cas9 in knocking out a gene of interest. Using these chemically stabilized sgRNAs facilitates multigene editing at the protein level, as demonstrated by successful knockout of both Siglec-3 and Siglec-7 using two fluorophores in conjunction with fluorescence-activated cell sorting. These results demonstrate the versatility of this modular platform for assembling sgRNAs from small, chemically modified strands to simultaneously disrupt the gene expression of two proteins.

Radiofluorination of an Anionic, Azide-Functionalized Teroligomer by Copper-Catalyzed Azide-Alkyne Cycloaddition.

This study describes the synthesis, radiofluorination and purification of an anionic amphiphilic teroligomer developed as a stabilizer for siRNA-loaded calcium phosphate nanoparticles (CaP-NPs). As the stabilizing amphiphile accumulates on nanoparticle surfaces, the fluorine-18-labeled polymer should enable to track the distribution of the CaP-NPs in brain tumors by positron emission tomography after application by convection-enhanced delivery. At first, an unmodified teroligomer was synthesized with a number average molecular weight of 4550 ± 20 Da by free radical polymerization of a defined composition of methoxy-PEG-monomethacrylate, tetradecyl acrylate and maleic anhydride. Subsequent derivatization of anhydrides with azido-TEG-amine provided an azido-functionalized polymer precursor (o14PEGMA-N3) for radiofluorination. The 18F-labeling was accomplished through the copper-catalyzed cycloaddition of o14PEGMA-N3 with diethylene glycol-alkyne-substituted heteroaromatic prosthetic group [18F]2, which was synthesized with a radiochemical yield (RCY) of about 38% within 60 min using a radiosynthesis module. The 18F-labeled polymer [18F]fluoro-o14PEGMA was obtained after a short reaction time of 2-3 min by using CuSO4/sodium ascorbate at 90 °C. Purification was performed by solid-phase extraction on an anion-exchange cartridge followed by size-exclusion chromatography to obtain [18F]fluoro-o14PEGMA with a high radiochemical purity and an RCY of about 15%.

Water-soluble chitotriazolans derived from cationic, neutral, and anionic common chitosan derivatives: Synthesis, characterization, and antibacterial activity

Partially substituted N,N,N-trimethyl chitosan (TMC), N-(2-(N,N,N-trimethylammoniumyl))acetyl chitosan (TAC), 2-hydroxy-3-(N,N,N-trimethylammoniumyl)propyl chitosan (HTC), N-(2-hydroxy)propyl chitosan (HPC), and N-carboxymethyl chitosan (CMC) were reacted with the diazo transfer reagent, imidazole-1-sulfonyl azide, to convert the 2-amino groups to azides. Subsequent reaction via copper-catalyzed azide-alkyne cycloaddition (CuAAC) with N-propargyl-N,N,N-trimethylammonium bromide provided water-soluble “mixed” chitotriazolan derivatives. The NMR data was generally consistent with the complete conversion of all primary amines in the polymer to triazole moieties, except in the case of TAC, where the conversion was ∼50 %. The mixed chitotriazolans derived from cationic TMC, TAC, and HTC and neutral HPC were active against Gram-positive S. aureus and E. faecalis and Gram-negative bacteria E. coli and P. aeruginosa, but chitotriazolans derived from anionic CMC were inactive.

Enolate-Azide [3 + 2]-Cycloaddition Reaction Suitable for DNA-Encoded Library Synthesis.

The DNA-encoded chemical library (DEL) is a powerful hit selection technique in either basic science or innovative drug discovery. With the aim to circumvent the issue concerning DNA barcode damage in a conventional on-DNA copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC), we have successfully developed the first DNA-compatible enolate-azide [3 + 2] cycloaddition reaction. The merits of this DEL chemistry include metal-free reaction and high DNA fidelity, high conversions and easy operation, broad substrate scope, and ready access to the highly substituted 1,4,5-trisubstituted triazoles. Thus, it will not only further enrich the DEL chemistry toolbox but also will have great potential in practical DEL synthesis.

New N-Methylimidazole-Functionalized Chitosan Derivatives: Hemocompatibility and Antibacterial Properties.

Novel imidazole derivatives of the low molecular weight chitosan N-(2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-1-methyl-1H-imidazol-3-ium chitosan chloride (NMIC) were synthesized using copper-catalyzed azide-alkyne cycloaddition (CuAAC). The degrees of substitution (DSs) for the new derivatives were 18-76%. All chitosan derivatives (2000 µg/mL) were completely soluble in water. The antimicrobial activity of the new compounds against E. coli and S. epidermidis was studied. The effect of chitosan derivatives on blood and its components was studied. NMIC samples (DS 34-76%) at a concentration <10 μg/mL had no effect on blood and plasma coagulation. Chitosan derivatives (DS 18-76%) at concentrations of ≥83 μg/mL in blood and ≥116.3 μg/mL in plasma resulted in a prolongation of the clotting time of blood and plasma, positively related to the DS. At concentrations up to 9.1 μg/mL, NMIC did not independently provoke platelet aggregation. The degree of erythrocyte hemolysis upon contact with NMIC samples (2.5-2500 μg/mL) was below 4%. The inhibition of blood/plasma coagulation indicates the promising use of the studied samples to modify the surface of medical materials in order to achieve thromboresistance.

Exploring Lignification Complexity in Plant Cell Walls with Airyscan Super-resolution Microscopy and Bioorthogonal Chemistry.

In this paper, we present the use of multiplex click/bioorthogonal chemistry combined with super-resolution Airyscan microscopy to track biomolecules in living systems with a focus on studying lignin formation in plant cell walls. While laser scanning confocal microscopy (LSCM) provided insights into the tissue-scale dynamics of lignin formation and distribution in our previous reports, its limited resolution precluded an in-depth analysis of lignin composition at the unique cell wall or substructure level. To overcome this limitation, we explored the use of Airyscan microscopy, which, among the super-resolution techniques available, offers an optimal balance between performance, cost, accessibility, and ease of implementation. Our study demonstrates that a triple labeling strategy using copper-catalyzed azide-alkyne cycloaddition (CuAAC), strain-promoted azide-alkyne cycloaddition (SPAAC), and inverse electronic-demand Diels-Alder cycloaddition (IEDDA) to label modified lignin metabolic precursors can be combined with Airyscan microscopy to reveal the zones of active lignification at the single cell level with improved sensitivity and resolution. This approach enables insights into the lignin composition in wall substructures, such as pits or in wall layers that are otherwise not distinguishable by classical LSCM. Our work emphasizes the importance of studying lignin formation in plant cell walls and demonstrates the potential of combining bioorthogonal chemistry and super-resolution microscopy techniques for studying biomolecules in living systems.

A Polyoxometalate-Based Pathologically Activated Assay for Efficient Bioorthogonal Catalytic Selective Therapy.

Since polyoxometalates (POMs) can undergo reversible multi-electron redox transformations, they have been used to modulate the electronic environment of metal nanoparticles for catalysis. Besides, POMs possess unique electronic structures and acid-responsive self-assembly ability. These properties inspire us to tackle the drawbacks of the well-known copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction when applied in biomedical applications, such as low catalytic efficiency and unsatisfactory disease selectivity in living systems. Herein, we construct the molybdenum (Mo)-based POM nanoclusters doped with Cu (Cu-POM NCs) as a highly efficient bioorthogonal catalyst, which is responsive to pathologically acid and H2S for selective antibiofilm therapy. Leveraging the merits of POM, the Cu-POM NCs exhibit biofilm-responsive self-assemble behavior, efficient CuAAC reactions-mediated in situ synthesis of antibacterial molecules, and NIR-II photothermal effect selectively triggered by H2S in pathogens. It should be noted that the consumption of bacterial H2S at the pathological site by Cu-POM NCs extremely decreases the number of persister bacteria, which is conducive to the inhibition of bacterial tolerance and elimination of biofilms. Unlocked at pathological sites and endowed with NIR-II photothermal property, the constructed POM-based bioorthogonal catalytic platform provides new insights into the design of efficient and selective bioorthogonal catalysts for disease therapy.

Synthesis and biological evaluation of carbohydrate-Coumarin/vanillic acid hybrid as a promising antiparasitic agent

Leishmaniasis is caused by infection with the protozoan parasites Leishmania. It is classified as one of the most significant neglected tropical diseases. It remains a significant global public health concern. Current treatments include the use of pentavalent antimonial, amphotericin B, pentamidine, miltefosine, and paromomycin. However, several limitations such as toxicity, side effect, and resistance to these drugs of certain species are of concern. To combat this disease, effective chemotherapy is urgently required for its treatment and management. In this study, we synthesized a series of carbohydrate-coumarin/vanillic acid hybrids linked through triazole moiety via CuACC (Copper-catalysed azide-alkyne cycloaddition) reaction. These compounds were evaluated for their in vitro antiparasitic activity using MTT assay against Leishmania donovani whereas, all compounds show IC50 value in the range of 65–74 μM.

Phosphorus fluoride exchange: Multidimensional catalytic click chemistry from phosphorus connective hubs

Phosphorus Fluoride Exchange (PFEx) represents a cutting-edge advancement in catalytic click-reaction technology. Drawing inspiration from Nature's phosphate connectors, PFEx facilitates the reliable coupling of P(V)-F loaded hubs with aryl alcohols, alkyl alcohols, and amines to produce stable, multidimensional P(V)-O and P(V)-N linked products. The rate of P-F exchange is significantly enhanced by Lewis amine base catalysis, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). PFEx substrates containing multiple P-F bonds are capable of selective, serial exchange reactions via judicious catalyst selection. In fewer than four synthetic steps, controlled projections can be deliberately incorporated along three of the four tetrahedral axes departing from the P(V) central hub, thus taking full advantage of the potential for generating three-dimensional diversity. Furthermore, late-stage functionalization of drugs and drug fragments can be achieved with the polyvalent PFEx hub, hexafluorocyclotriphosphazene (HFP), as has been demonstrated in prior research.

Hybrid pyrazoline-triazole fluorescent dyes: Synthesis, photophysics, electrochemical, and antioxidative activity

A four-step reaction method to synthesize a new series of 1-benzyl-4-((2-(1,5-diaryl-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)methyl)-1H-1,2,3-triazoles (5) and their photophysical and electrochemical evaluation is reported herein. The synthetic method comprises: (i) Michael condensation between 2-hydroxy-acetophenone and aryl aldehydes to obtain chalcones, (ii) a [3 + 2] cyclocondensation reaction involving chalcones and phenylhydrazine to reach the 2-pyrazolines (1), (iii) an O-alkylation reaction of 1 with propargyl bromide (2) to give O-propargylated 2-pyrazolines 3, and (iv) standard copper-catalyzed azide-alkyne cycloaddition (CuAAC) involving benzyl azide (4) and 2-pyrazolines 3 to furnish the desired triazole series (5) as a new hybrid polycyclic system at total yields of up to 51%. Steady-state fluorescence emission exhibited a band in the blue region when excited at the least energetic transition of each compound, with varying values of fluorescence quantum yields (Φf) and Stokes Shift (SS), according to solvent polarity. In the solid state, the compounds showed similar behavior to the study of the absorption and emissive properties in solution. TD-DFT calculations revealed that all compounds had delocalized electron density along the pyrazoline unit and were not influenced by the attached substituent or change in solvent polarity. In addition, electrochemical and DPPH antioxidant analyses were performed.

Two-Step Validation Approach for Tools To Study the DNA Repair Enzyme SNM1A.

We report a two-step validation approach to evaluate the suitability of metal-binding groups for targeting DNA damage-repair metalloenzymes using model enzyme SNM1A. A fragment-based screening approach was first used to identify metal-binding fragments suitable for targeting the enzyme. Effective fragments were then incorporated into oligonucleotides using the copper-catalysed azide-alkyne cycloaddition reaction. These modified oligonucleotides were recognised by SNM1A at >1000-fold lower concentrations than their fragment counterparts. The exonuclease SNM1A is a key enzyme involved in the repair of interstrand crosslinks, a highly cytotoxic form of DNA damage. However, SNM1A and other enzymes of this class are poorly understood, as there is a lack of tools available to facilitate their study. Our novel approach of incorporating functional fragments into oligonucleotides is broadly applicable to generating modified oligonucleotide structures with high affinity for DNA damage-repair enzymes.

Preparation and Biological Properties of Oligonucleotide-Functionalized Virus-like Particles.

Oligonucleotides are powerful molecules for programming function and assembly. When arrayed on nanoparticle scaffolds in high density, the resulting molecules, spherical nucleic acids (SNAs), become imbued with unique properties. We used the copper-catalyzed azide-alkyne cycloaddition to graft oligonucleotides on Qβ virus-like particles to see if such structures also gain SNA-like behavior. Copper-binding ligands were shown to promote the click reaction without degrading oligonucleotide substrates. Reactions were first optimized with a small-molecule fluorogenic reporter and were then applied to the more challenging synthesis of polyvalent protein nanoparticle-oligonucleotide conjugates. The resulting particles exhibited the enhanced cellular uptake and protection from nuclease-mediated oligonucleotide cleavage characteristic of SNAs, had similar residence time in the liver relative to unmodified particles, and were somewhat shielded from immune recognition, resulting in nearly 10-fold lower antibody titers relative to unmodified particles. Oligonucleotide-functionalized virus-like particles thus provide an interesting option for protein nanoparticle-mediated delivery of functional molecules.

Synthesis of AB2 type hyperbranched polymer by CuAAC based 1,3-dipolar cycloaddition and its application in delivering curcumin to cancer cell cultures in-vitro

Hyperbranched polymers are three-dimensional macromolecules with unique physical and chemical properties, such as high solubility, low viscosity, and many functional groups at the terminals, as well as possible applications in several fields. Herein, we report the synthesis of a trifunctional AB2 monomer in a three-step process followed by "Click" polymerization via copper-catalyzed azide-alkyne cycloaddition to prepare a polytriazole-based hyperbranched polymer. Synthesized monomer and polymer were subsequently characterized by 1H and 13C NMR spectroscopy, and size-exclusion chromatography. The AB2 type hyperbranched polymer was self-assembled into lipid-polymer hybrid nanoparticles (HBP-NPs) through a nanoprecipitation approach, and curcumin (CUR) was incorporated into the HBP-NPs. The CUR-loaded HBP-NPs were characterized by particle size analysis, zeta potential, polydispersity index, morphology, drug entrapment efficiency, in vitro drug release, cellular uptake, and anticancer potential against HepG2 and NCI-H460 cell lines. The results indicated the CUR-loaded HBP-NPs demonstrated enhanced cell inhibition due to the improved delivery of CUR upon incorporation into HBP-NPs.

Harnessing the power of PLA-PEG nanoparticles for Linezolid delivery against methicillin-resistant Staphylococcus aureus

This study deals with the development of novel poly(lactic acid)-poly(ethylene glycol) nanoparticles (PLA-PEG NPs) for the efficient and prolonged delivery of Linezolid (LNZ), a synthetic antibacterial agent used against methicillin-resistant Staphylococcus aureus (MRSA). A two-step synthetic strategy based on carbodiimide coupling and copper-catalyzed azide-alkyne cycloaddition was first exploited for the conjugation of PLA with PEG. The encapsulation of LNZ into medium-molecular-weight PLA-PEG NPs was carried out by different methods including nanoprecipitation and dialysis. The optimal PLA-PEG@LNZ nanoformulation resulted in 3.5% LNZ payload (15% encapsulation efficiency, with a 10:3 polymer to drug mass ratio) and sustained release kinetics with 65% of entrapped antibiotic released within 80 h. Moreover, the zeta potential values (from −31 to −39 mV) indicated a good stability without agglomeration even after freeze-drying and lyophilization. The PLA-PEG@LNZ NPs exerted antimicrobial activity against a panel of Gram-positive bacteria responsible for human infections, such as Staphylococcus aureus including MRSA, Staphylococcus epidermidis, Staphylococcus lugdunensis and vancomycin-resistant Enterococcus faecium (VREfm). Moreover, PLA-PEG@LNZ NPs showed inhibitory activity on both planktonic growth and preformed biofilm of MRSA. The antibacterial activity of LNZ incorporated in polymeric NPs was well preserved and the nanosystem served as an antibiotic enhancer with a potential role in MRSA-associated infections management.