- Open Access
Susceptibility of microbial cells to the modified PIP2-binding sequence of gelsolin anchored on the surface of magnetic nanoparticles
© The Author(s) 2019
- Received: 30 January 2019
- Accepted: 26 June 2019
- Published: 8 July 2019
Magnetic nanoparticles (MNPs) are characterized by unique physicochemical and biological properties that allow their employment as highly biocompatible drug carriers. Gelsolin (GSN) is a multifunctional actin-binding protein involved in cytoskeleton remodeling and free circulating actin sequestering. It was reported that a gelsolin derived phosphoinositide binding domain GSN 160–169, (PBP10 peptide) coupled with rhodamine B, exerts strong bactericidal activity.
In this study, we synthesized a new antibacterial and antifungal nanosystem composed of MNPs and a PBP10 peptide attached to the surface. The physicochemical properties of these nanosystems were analyzed by spectroscopy, calorimetry, electron microscopy, and X-ray studies. Using luminescence based techniques and a standard killing assay against representative strains of Gram-positive (Staphylococcus aureus MRSA Xen 30) and Gram-negative (Pseudomonas aeruginosa Xen 5) bacteria and against fungal cells (Candida spp.) we demonstrated that magnetic nanoparticles significantly enhance the effect of PBP10 peptides through a membrane-based mode of action, involving attachment and interaction with cell wall components, disruption of microbial membrane and increased uptake of peptide. Our results also indicate that treatment of both planktonic and biofilm forms of pathogens by PBP10-based nanosystems is more effective than therapy with either of these agents alone.
The results show that magnetic nanoparticles enhance the antimicrobial activity of the phosphoinositide-binding domain of gelsolin, modulate its mode of action and strengthen the idea of its employment for developing the new treatment methods of infections.
- PBP10 peptide
- Magnetic nanoparticles
- Fungal cells
In the past decade, surface modified magnetic nanoparticles composed of an iron oxide core and a metallic or polymeric shell have received attention as potential nanomaterials that might be used in theranostic applications, for example as drug transporters, inducers of magnetic hyperthermia, MRI contrast agents and separators and trackers of macromolecules [1–4]. Many studies have focused on the development of an efficient and repeatable synthesis process to obtain size- and shape-controlled monodisperse and biocompatible nanoparticles . For this purpose, different methods such as co-precipitation, thermal decomposition, microemulsion, sol–gel synthesis, and green synthesis using plant or bacterial extracts have been proposed . Most of the previous work was directed to obtain a nanostructure with a specific shape via one-pot synthesis [7–9].
The physicochemical properties of nanomaterials exert a strong impact on their biomedical applications and therapeutic properties. Such parameters as size, shape and surface charge determine nanoparticle stability and dispersity which in turn regulate biological effects and influence surface interactions, cellular uptake and delivery processes . Nanoparticle surface chemistry partially defines their interaction with bioactive agents used during the functionalization process as well as their biological effects [11, 12]. The conjugation process might be realized via physical or chemical interactions. Attachment-based physicochemical phenomena include ionic and hydrophobic interactions and dative bonding, which engages gold surface conduction electrons. Chemisorption via thiol derivatives can occur by the bifunctional linker carbodiimide (EDC)/active esters (NHS—N-hydroxy-succinimide) or by adapter molecules like avidin and biotin [13, 14]. In the case of a terminal amine group present on the surface, non-covalent (hydrogen bonding, ionic, electrostatic) and covalent (imine, enamine, peptide bond etc.) bonds can be engaged to attach bioactive agents [15, 16].
Gelsolin (GSN) belongs to a family of proteins that have the ability to bind and shorten actin filaments and are regulated by phosphoinositides such as phosphatidylinositol 4,5 bisphosphate (PIP2), sphingosine 1-phosphate (S1P) and by lysophosphatidic acid (LPA) . It is composed of a chain of 730 amino acids, organized in six homologous segments G1-G6, each of which is responsible for different protein functions . PBP10 peptide (GSN 160–169) is derived from the corresponding GSN PIP2-binding sequence, which, when coupled to rhodamine B, shows antibacterial activity against both Gram-positive and Gram-negative bacteria . In addition, it was found that intact GSN and PBP10 bind to major constituents of the bacteria cell wall, such as lipopolysaccharides (LPS) and lipoteichoic acid (LTA) suggesting that this GSN domain might be engaged in bacteria targeting [20–22]. This possibility is reinforced by preferential gelsolin binding to structurally similar bioactive phospholipids that regulate the intracellular activity of GSN, i.e. phosphatidylinositols (PIP, PIP2) and. The structural similarity of LPS, LTA, LPA, and PIP2 is mostly caused by the presence of phosphorylated saccharides substituted with terminal acyl chains.
In this study we investigated the antimicrobial properties of gold and aminosilane coated magnetic nanoparticles in combination with derivatives of a PBP10 peptide including the native peptide (PBP10), a peptide with an additional amino acid, cysteine, functionalized by rhodamine B (Cys-PBP10-RhB) and a peptide functionalized by rhodamine B (PBP10-RhB). Their antibacterial activity was measured against representative bacteria (Staphylococcus aureus MRSA Xen 30, Pseudomonas aeruginosa Xen 5) and fungal cells (Candida albicans, Candida glabrata and Candida tropicalis). We demonstrate that co-treatment of the planktonic form of pathogens and those embedded in biofilm matrix by PBP10 derivatives in combination with magnetic nanoparticles is more effective than therapy with either of these agents alone. Moreover, we show that MNPs might modulate the antimicrobial properties of the native peptide, which in free form does not exert a bactericidal effect. These findings demonstrate magnetic nanoparticles as a promising sensitizer that can enhance the antimicrobial effects of short cationic peptides.
Synthesis of peptide-functionalized magnetic nanoparticles
Magnetic nanoparticles were created using previously published procedures with some modification . Briefly, iron-oxide cores were obtained via modification of Massart’s method, which is based on a co-precipitation procedure of iron chloride salts. Gold functionalized nanoparticles were synthesized using a modification of the K-gold procedure. Aminosilane shells were obtained by one-step polycondensation of 3-aminopropyl-methoxy silane (APTMS). In both procedures, the nanoparticles were washed three times with water and ethanol, then dried in an oven at 50 °C into a powder . In the next step, nanoparticles were re-suspended in phosphate buffered saline (PBS) and each peptide derivative was added in equal concentration and incubated for nucleation and growth for 48 to 72 h . The native polycationic PBP10 peptide, which represents a 10 amino acid sequence from PIP2 binding site of human gelsolin 160–169 (QRLFQVKGRR) and the membrane-permeant polycationic peptide PBP10 linked to rhodamine B (RhB- QRLFQVKGRR) were from Lipopharm, (Gdańsk, Poland). The peptide with an additional amino acid, cysteine, (Cys-PBP10-RhB) was a gift from Dr R. Vagners (Peptide Synthesis Laboratory, Organiskas Sintezes Instituts, Riga, Republic of Latvia).
Characterization of peptide-functionalized magnetic nanoparticles
The chemical structure and morphology of the synthesized nanosystems were evaluated by a number of techniques. All FT-IR spectra were registered in the wavenumber range of 4000 to 500 cm−1 by co-adding 32 scans with a resolution of 4 cm−1. Differential scanning calorimetry (DSC) was recorded on a DSC Discovery (TA Instruments, USA). Nitrogen was used as a purge gas with a flow of 10 mL/min. Nanosystems (2 mg) were placed in aluminum pans and heated from 25 to 500 °C, with a heating rate of 5 °C/min. Transmission electron microscopy TEM/EDX (Tecnai G2 X-TWIN) was used to characterize the morphology of the MNPs. SEM images were obtained using a scanning electron microscope (FEI Inspect S50). Crystalline (XRD) analysis was made using an X-ray diffractometer (Bruker D8 Advanced).
The antibacterial activity of agents alone (PBP10, Cys-PBP10-RhB, and PBP10-RhB) or in combination with MNPs (MNP@Au and MNP@NH2) were tested against P. aeruginosa Xen 5 and S. aureus Xen 30. Bacteria were grown to mid-log phase at 37 °C, then resuspended in LB and brought to 109 CFU/mL (OD600 ~ 0.5–0.8). Next, 100 µL of bacteria suspension were added to each well at a concentration range of 5–50 µg/mL. Changes in bacterial chemiluminescence intensity were monitored within 1 h and performed using a Labsystem Varioscan Lux (Thermo Scientific). P. aeruginosa Xen 5 and S. aureus Xen 30 were incubated with different concentrations (5, 10, 20 and 50 µg/mL) of compounds to evaluate their effect on the formation of biofilm. After 48 h incubation, the medium was removed and the wells were washed in order to remove planktonic cells. Biofilm mass was stained using 0.1% (w/v) crystal violet (CV). After a 15 min incubation, the unbound dye was removed, and the plates were thoroughly rinsed. Biofilm mass was spectrophotometrically measured at a wavelength of 580 nm and the results were compared with the values obtained in the control.
To evaluate the fungicidal activity, killing assays were performed against clinical strains of Candida spp. (C. albicans, C. glabrata and C. tropicalis) isolated from a patient diagnosed with local mycosis as described previously . Briefly, Candida cells were grown to mid-log phase at 37 °C, re-suspended in PBS, and brought to 108 CFU/mL (OD600 = 0.5) and then 100 µL was added to 10 mL of PBS. Fungal cells were then added to PBS containing different concentrations agents and incubated 1 h at 37 °C. Next, the plates were transferred to ice, and suspensions were diluted 10- to 1000-fold in PBS. 10 μL aliquots were spotted on Sabouraud dextrose agar plates for overnight culture at 37 °C for CFU determination. In another set of experiments, a resazurin based assay was performed. Changes in fluorescence (ex520/em590 nm) during a 5 h incubation of Candida spp. (OD600 = 0.1) in the presence of the tested peptide in free and immobilized forms (at a concentration range of 10–50 μg/mL) were measured as an additional method to assess cell proliferation and kinetics of growth (Labsystems Varioscan Lux, Thermo Scientific).
To assess the ability to prevent the formation of biofilm, Candida spp. cells were grown for 48 h at 37 °C in the presence of peptide derivatives. After incubation, each well was washed with PBS to remove planktonic cells. Biofilm mass was evaluated using the crystal violet (CV) staining (0.1%) method. The unbound stain then was rinsed out with water and extracted with ethanol (70%, 100 μL), then the optical density of extract (OD) was measured at 580 nm.
Atomic force microscopy (AFM)
A clinical isolate of C. albicans was resuspended in distilled water (OD600 = 0.15) and incubated with PBP10 derivatives in free and immobilized forms at 20 μg/mL. Then, 50 µL was spotted on a mica surface that was previously functionalized by 5% (3-aminopropyl) triethoxysilane (APTES) until completely dry. Atomic force microscope (AFM) measurements were performed directly. Images were collected using a Nano Wizard 4 BioScience AFM (JPK Instruments, Germany) working in contact and Quantitative Imaging (QI) mode. MLCT (Bruker) triangular pyramid-shaped tips with a nominal spring constant equal to 0.1 N/m were employed. Initially, the tip was brought into contact with the surface of a fungal cell until a given deflection of the cantilever was reached. The scanning was then started with a constant velocity of 2 µm/s. The three signals were recorded simultaneously while scanning the sample surface: topography, vertical deflection and lateral deflection of the cantilever, with a resolution of 128 pixels per line. Topography images serve as a qualitative assessment while vertical and lateral deflection uncover surface features with better clarity. Due to the softness of fungal cell after incubation and lateral forces during contact mode scanning, a force curves-based imaging mode was used (QI mode) with the resolution of 128 pixels per line, using the same cantilever. We only show images from vertical deflection and QI mode.
Inner membrane (IM) permeabilization assay
IM permeabilization was evaluated by measuring the release of cytoplasmic β-galactosidase activity from Candida spp. using ONPG (ortho-nitrophenyl-β-d-galactopyranoside) as the substrate . Fungal cells were resuspended in a PBS (OD 600 = 0.1). Next, to 100-μL of Candida cells, various concentrations of agents (5, 10 and 50 µg/mL) were added and mixed with 10 μL of ONPG (30 mM) in a 96-well plate. The production of o-nitrophenol during 2 h was determined by monitoring the change in absorbance at 420 nm using Labsystem Varioskan Lux (Thermo Scientific) spectrophotometer.
Synthesis and physicochemical properties of peptide functionalized magnetic nanoparticles
Peptide-functionalized magnetic nanoparticles affect the metabolism and formation of bacterial biofilm
Next, we explored the potential of magnetic nanoparticles to increase the ability of PBP10 peptide derivatives to prevent biofilm formation. Panels g–l of Fig. 2 illustrate that PBP10 derivatives alone are able to prevent biofilm formation in both strains. However, to obtain inhibition of biofilm formation in the 30–60% range, application of a high dose of peptides (50 µg/mL) is required. Addition of nanoparticles allows us to accomplish this with smaller doses. For example, when combined with gold decorated MNPs, treatment with 10 µg/mL peptide derivatives decreases biofilm formation by 60% for all PBP10 derivatives for P. aeruginosa, 60% for PBP10 and PBP10-RhB, and 90% for Cys-PBP-RhB in the case of biofilm formed by S. aureus.
Magnetic nanoparticles modulate fungal killing properties of PBP10 derivatives
Magnetic nanoparticles increase anti-biofilm activity of tested peptides
Peptide-functionalized magnetic nanoparticles induce disruption of membrane integrity and leakage of cytoplasmic components
In our study, we revealed that magnetic nanoparticles significantly elevated the sensitivity of microbial cells to the effects of PBP10 derivatives. We observed increased activity of GSN derived peptides in a killing assay against planktonic bacterial and fungal cells and a better ability to interrupt biofilm formation when anchored on the surface of nanoparticles. MNPs improved the fungicidal effect of peptides through disruption of the fungal membrane and facilitated peptide transport into cells. Moreover, the designed nanosystems prevent cell division. This finding provides evidence that nanoparticles might be a promising sensitizer of pathogenic cells, and, nanostructures have potential as enhancers of fungal infection treatment. The formulation presented in this report might be useful for creating a general pattern to improve peptide efficacy via immobilization procedure.
Currently, to treat infections, antibiotics are still the main therapeutic option , but misuse of antibiotics, including their massive application for prophylactic purposes without proper medical indication, causes strain selection and development of multidrug resistance patterns [30–32]. Unfortunately, antibiotic resistance is a dynamic, social and global problem, both in the case of bacterial and fungal pathogens . Moreover, the number and diversity of chemical structures of currently available antibacterial drugs are much higher than the number of active substances in relation to pathogenic fungi. The appearance of MDR strains, with resistance to many groups of antimicrobial agents, creates the need to design new therapeutic strategies for successful treatment of infectious diseases [34, 35].
Antimicrobial peptides (AMPs) are a class of antimicrobial agents with a broad spectrum of protective, antimicrobial features . In effect, they are a viable alternative to currently used antibiotics [37, 38]. However, they are sensitive to protease degradation and are inactivated in the presence of various polyelectrolyte factors that occur at sites of infection including F-actin, DNA and bacteriophage [26, 39, 40]. Moreover, they exert high toxicity on human host cells and cause hemolytic activity . Additionally, AMPs isolated from natural sources are usually in insufficient quantity. Therefore, to obtain an adequate amount, chemical synthesis is often implemented, which is expensive . These AMP disadvantages might restrict their clinical use. Due to this fact, significant efforts and different strategies have been engaged in the past decades to protect AMPs from degradation, inactivation and to improve their biocompatibility including by substitution with unnatural amino acids, d-amino acids, W or end-caps, varying chain length, cyclization or polymerization [43–45]. Another approach to increasing clinical use is through increasing stability and by decreasing their toxicity through the use of drug carriers . Our previous studies have shown that both physical and covalent immobilization on the nanoparticle surface markedly enhances the activity of AMPs and their chemical analogs [23, 47]. Moreover, the embedding process prolonged in vitro peptide activity [48, 49]. Application of nanoparticles as drug carriers, during systemic injection, shows that nanosystems functionalized by homing molecules increase particle elimination with protection against non-specific organ accumulation in healthy mice as well as offer an improvement in cancer therapy due to elongated retention of MNPs in the tumor site . This supports the assertion that compared to a traditional form of therapy, use of nanoparticles as a drug delivery system improves the pharmacokinetic profile of the active substance, leads to enhancement of the anticancer/antimicrobial effect, and reduces side effects and systemic toxicity .
Herein, we propose the application of nanoparticles as a drug delivery system for PBP10 peptides. Those fragments possess unique properties including positive charge and hydrophobicity, which are enhanced by to rhodamine B conjugation. RhB-functionalized derivatives enter passively into cells and disrupt cellular pathways that depend on phosphoinositide signaling. However, un-functionalized PBP10 derivatives do not exert the above effects, but if anchored to nanoparticles, desired targets can be achieved. The pathogen-killing process is rapid and involves the destruction of the plasma membrane, disruption of metabolic pathways and inhibition of proliferation. Furthermore, our studies show that synthesized nanosystems are more efficient than free peptide. PBP10 derivatives’ mode of action does not include pore formation during interaction with bacterial membranes, despite their similarity to antimicrobial peptides through the following features: short sequence, net positive charge, helical structure and amphipathic nature [19, 52]. PBP10 targets the bacteria cell wall via interaction with LPS and LTA due to the chemical similarity of these compounds to PIP2. In the case of nanoparticles, their target points involved in microbial killing include internalization in the pathogen cell wall and membrane, generation of reactive oxygen species, and creation of small pores in the bacteria cell wall [53–56]. This process enhances the uptake of active agents, oxidative damage of macromolecules and oozing of cytoplasmic content [57–59]. Therefore besides the fact that they can be used for the delivery of conventional or novel active agents, they possess intrinsic antimicrobial activity. Published data show that they are able to avoid drug resistance mechanisms in bacterial and fungal cells via different strategies including: (i) inhibition of the activity of efflux pumps; (ii) restriction of biofilms formation due to penetration and/or induction of hyperthermia processes; (iii) interference of quorum sensing; (iv) inactivation of enzyme and (v) possibly plasmid curing [60–63]. Moreover, our recent study demonstrated that PBP10-containing nanosystems exert strong anti-inflammatory and immunomodulatory activities with the ability to limit the LPS-induced cellular effects, which additionally strengthen the potential of PBP10 magnetic derivatives as protective antimicrobial agents .
Additionally, the presence of peptide on the surface of magnetic nanoparticles is crucial in nanosystem stabilization. Based on the findings here, we suggest that PBP10 derivatives can act as a capping agent. This kind of compound plays a key role in the inhibition of particle aggregation; in effect, they control the particle growth and structural stability . The above features are required to preserve nanosystem properties in the presence of body fluids, potentiate their antimicrobial activity and enhance active molecules delivery .
In conclusion, the data presented in this study clearly indicate that magnetic nanoparticles enhance the antimicrobial properties of GSN derived peptides. We showed that type of interaction (electrostatic/chemisorption) between the nanoparticle surface and the bioactive agents might determine the biological efficiency of the nanosystem. Additionally, we suggest that synthesized nanoparticles could be used as a sensitizer for fungal cells to enhance the therapeutic effect of peptides. This nanoformulation might create new approaches and provide a general platform for developing new treatment options against microbial infection.
This work was financially supported by the National Science Center, Poland under Grant: UMO-2015/17/B/NZ6/03473 (to RB), by the General Medicine Institute of the USA through grant GM111942 (PAJ), and by Medical University of Bialystok (N/ST/ZB/18/003/1162 to PD). Part of the study was conducted with the use of equipment purchased by the Medical University of Białystok as part of the RPOWP 2007–2013 funding, Priority I, Axis 1.1, contract No. UDA-RPPD.01.01.00-20-001/15-00 dated 26.06.2015 and in Centre of Synthesis and Analysis BioNanoTechno of the University of Bialystok (POPW.01.03.00-20-034/09-00 and POPW.01.03.00-20-004/11 projects).
RB: designed, supervised the research, gave suggestions on the experiments, helped to draft the manuscript, KNL: evaluated the antimicrobial activity of PBP10-containing nanosystems in different experimental settings, helped to draft the manuscript, PD: evaluated the candidacidal activities of tested agents using AFM, helped to draft the manuscript, AZW: carried out the physicochemical analysis of developed nanosystems, helped to draft the manuscript, PM: participated in physicochemical analysis of developed nanosystems, BD: analyzed bactericidal data from experiments, helped to draft the manuscript; KF: gave suggestions on the experiments, analyzed data from experiments, helped to draft the manuscript, EP: participated in AFM-based analyses, helped to draft the manuscript, JM: gave the suggestions about AFM-based experiments, helped to draft the manuscript, PAJ: supervised the research and writing of the manuscript. All authors read and approved the final manuscript.
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The authors declare that they have no competing interests.
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