Mannose-Modificated Polyethylenimine: A Specific and Effective

Article Cite This: Langmuir 2018, 34, 1574−1580

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Mannose-Modificated Polyethylenimine: A Specific and Effective Antibacterial Agent against Escherichia coli Mei Liu,*,† Jiao Li,† and Baoxin Li*,‡ †

Key Laboratory of Analytical Chemistry for Life Science of Shaanxi Province, College of Food Engineering and Nutritional Science and ‡Key Laboratory of Analytical Chemistry for Life Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi’an 710119, China

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S Supporting Information *

ABSTRACT: Polyethylenimine (PEI) has antimicrobial activity against Gram-positive (Staphylococcus aureus, S. aureus) and Gram-negative (Escherichia coli, E. coli), bacteria but is highly cytotoxic, and the selective antimicrobial activity against S. aureus is obviously better than that against E. coli. To reduce the cytotoxicity and improve the antibacterial activity against E. coli, we modified PEI with D-mannose through nucleophilic addition between primary amine and aldehyde groups to get mannose-modified polyethylenimine copolymer particles (Man-PEI CPs). The use of mannose may provide good targeting ability toward E. coli pili. The antibacterial activity of Man-PEI CPs was investigated. Man-PEI CPs shows specific and very strong killing capability against E. coli at a concentration of 10 μg/mL, which is the highest antimicrobial efficiency compared to that of unmodified PEI (220 μg/mL). The antibacterial mechanism demonstrated that the enhancement in antibacterial activity is due to specific recognition of the mannose and destroying the cell wall of the bacteria by PEIs. Importantly, the Man-PEI CPs show less cytotoxicity and excellent biocompatibility. The results indicate that Man-PEI CPs have great potential as novel antimicrobial materials to prevent bacterial infections and provide specific applications for killing E. coli.

1. INTRODUCTION The prevalence of bacterial infectious diseases is one of the most common causes of morbidity in patients. After the emergence of antibiotics, they play a very important role in promoting medical and social development.1,2 However, multiple antibiotic-resistant bacteria have widely emerged among many species of pathogenic bacteria, which led to some antibiotics to no longer be effective in controlling infectious diseases.3 Discovering and designing new efficient antibacterial materials requires a considerable attention for the treatment of microbial disease.4−6 Among the antibacterial materials investigated, cationic polymers have emerged as a potential antibacterial material and have some obvious advantages, including a sustained inhibitory effect, broad-spectrum antibacterial features, and better biocompatibility compared to small molecular antibiotics.7−9 Kuroda’s group10 has investigated the antibacterial activity and cytotoxicity of conventional unmodified cationic polyethylenimine polymers (PEIs). They have found that the PEIs’ antibacterial activity against E. coli and S. aureus depended on both the PEIs’ architecture and molecular weight (MW). Furthermore, the low-MW PEIs are less cytotoxic to human cells than others, but the unmodified PEIs displayed selective activity against S. aureus over E. coli. This property of PEIs restricts its broad-spectrum antibacterial features, especially the antibacterial activity against E. coli. At present, a large number © 2018 American Chemical Society

of studies have focused on improving the antibacterial activity of PEIs. PEIs are mainly modified by covalent linkage with other components, such as surface-grafted quarternized PEI,11 functional-group-modified PEI microgels,12 PEI-functionalized silver nanoparticles,13 and phenylalanyl-integrated PEI.14 Although there has been some progress in enhancing the antibacterial activity of PEIs, these works do not involve the selective antibacterial activity and the cytotoxicity to cells of modified PEIs. On the other side, PEIs have been utilized as drug carriers in biomedical applications because of their ability to give high gene transfection efficiency, but they are highly cytotoxic.15−17 There have been some efforts on how to abate the toxic effects of PEIs so as to provide their potential applications in gene delivery. Various modifications of PEI have been introduced to alter the surface charge characteristics of PEI,18 such as grafting PEI with poly(ethylene glycol),19 hyaluronic acid-PEI particles,20 chitosan-PEI,21 galactosylated PEI,22 and mannose PEI.23 However, most of these modifications were tedious without control over the composition and molecular structure and achieved variable success. To the best of our knowledge, the investigation on how to lower the cytotoxicity of PEIs and Received: October 12, 2017 Revised: December 25, 2017 Published: January 5, 2018 1574

DOI: 10.1021/acs.langmuir.7b03556 Langmuir 2018, 34, 1574−1580

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medium. After centrifugation at 6000 rpm for 2 min, the remaining E. coli was redispersed in 0.9% sodium chloride solution. 2.4. Antibacterial Activity Experiments. The antibacterial activity of PEI, Man-PEI CPs, was investigated by incubation with bacterial cells suspensions in PBS buffer (10 mM, pH 7.4). E. coli with a concentration of 3 × 104 cells·mL−1 was mixed with different concentrations of PEI or Man-PEI CPs. After incubating at 37 °C for 3 h, 100 μL of the bacterial suspension was spread onto the solid LB agar plate. The colony-forming units (CFU) were counted after 16 h of incubation at 37 °C. The sterilization rate was determined by the following formula

meanwhile improve specific antibacterial features is still limited. Therefore, there is a need to modify PEIs in an easy and wellcontrolled manner to establish that low-MW PEIs are likely to be less toxic while still exhibiting antibacterial behavior, especially against E. coli. E. coli is a typical pathogenic bacterium that is especially problematic because it takes only as few as 10 cells to infect humans and cause serious illnesses.24 It is worthy of investigation for the purpose of protecting humans and the environment. In this study, we examined the sterilization potential of Man-PEI CPs which was modified by D-mannose through facile nucleophilic addition chemistry between primary amine and aldehyde groups. The modification of PEIs resulted in a decrease in the cytotoxicity of PEI because the primary amine groups of PEI were substituted and exhausted by the carbohydrate. Furthermore, the use of mannose may also provide a targeting ability toward E. coli through specific and multivalent interactions between the mannose on Man-PEI CPs and FimH lectin pili on the surface of E. coli.25 Man-PEI CPs exhibit good biocompatibility, low cytotoxicity, and efficient antibacterial ability, demonstrating a safe antibacterial property in the application of healthcare.

sterilization rate% = (C0 − C)/C0 × 100% where C is the CFU of the experimental group treated with PEI or Man-PEI CPs and C0 is the CFU of the control group without any treatment. 2.5. Fluorescence Microscope Measurements. The antibacterial efficiency of PEI or Man-PEI CPs was also proved by fluorescence microscopy. After treating suspensions of E. coli with PEI or Man-PEI CPs (the final concentration, 10 μg mL−1) at 37 °C for 3 h and staining them with PI for 15 min, the bacteria were separated by centrifugation at 6000 rpm for 10 min and then precipitate was resuspended in 20 μL of PBS buffer (10 mM, pH 7.4). Fluorescence microscope samples were obtained by adding 10 μL of the preprepared mixed suspensions to clean glass slides and covering them with coverslips for immobilization. The color of PI is red, and the type of light filter is a BP 540−585 nm exciter and DM 595 nm emitter. Magnification of the object lens is 40×. 2.6. Cell Viability Assay. Cytotoxicity against HeLa cells was evaluated according to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method.27 HeLa cells were seeded into a 96-well plate at a density of 1.0 × 103 cells per well in 100 μL of Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum and incubated for 12 h at 37 °C in 5% CO2. The PEI and Man-PEI CPs were diluted with DMEM and added to wells at final concentrations of 10, 50, 100, 250, and 500 μg mL−1, with three replicates of each concentration. After culturing for 24 h, the cells were washed with PBS, and a 20 μL aliquot of MTT was then added to each well to remove PEI and Man-PEI CPs. Finally, the MTT was removed, and any formazan that formed was dissolved with dimethyl sulfoxide (DMSO) after 15 min of shaking. Absorption was measured at a wavelength of 490 nm.

2. MATERIALS AND METHODS 2.1. Materials and Measurements. Branched PEI (MW = 600, 1800, 10 000, 99%), D-mannose, and ascorbic acid were purchased from Aladdin Ltd. (Shanghai, China). 3-(4,5-Dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) was purchased from Sigma Chemical Company. The propidium iodide (PI) was purchased from Solarbio Ltd. (Beijing, China). The bacterial medium components and phosphate-buffered saline (PBS, pH 7.4) were purchased from Sangon Biotech Co., Ltd. (Shanghai, China). The DMEM medium was purchased from HyClone Thermofisher (Beijing, China). E. coli K-12 and Staphylococcus aureus were purchased from the China General Microbiological Culture Collection Center (Beijing, China). Human cervix adenocarcinoma cells (HeLa) were purchased from KeyGen Biotech. Co. Ltd. (Nanjing, China). All other chemicals were of analytical reagent grade and used without further purification. UV−vis adsorption spectra were recorded on a U-3900H UV−vis spectrophotometer (Hitachi, Japan). Fluorescence spectra were measured on an F-4600 spectrometer (Tokyo, Japan). Scanning electron microscope (SEM) measurements were performed with a FEI Quanta 200 scanning electron microscope (FEI, America). The nuclear magnetic resonance (NMR) spectra were collected on a Bruker AVANCE III 600 (600 MHz) (Bruker, Germany) with the freeze-dried product dissolved in D2O. Fluorescent images were recorded on a fluorescence microscope (Olympus, FV1200). 2.2. Synthesis of Man-PEI Copolymer Particles. The synthesis method of Man-PEI CPs was carried out according to a previously reported procedure with slight adjustments.26 1 mL of PEI (0.1 g mL−1) was first dissolved in 7 mL of PBS buffer (10 mM, pH 7.4) by stirring for about 1 min, and then 2 mL of mannose (0.1 M) was added. Subsequently, after vigorous stirring for 1 min, the mixture was held at 90 °C for 40 min via hydrothermal treatment. Then the ManPEI CPs solutions were dialyzed against ultrapure water for 24 h through a dialysis bag (MWCO = 500 Da). The products inside the dialysis bag were collected for further study. In addition, PEI was modified with ascorbic acid to construct AA-PEI CPs according to the same method. 2.3. Bacterial Cultivation. E. coli bacterial samples were transferred from a −80 °C refrigerator onto agar slants (25 g of lysogeny broth and 15 g agar were dissolved in 1 L of water) and incubated at 37 °C for 16 h and then held at 4 °C for up to 2 weeks. A single colony from the slants was cultured overnight in a 20 mL sterile medium for 14 h in a shaker at 37 °C. After growth, the original E. coli was washed with 0.9% sodium chloride solution twice to remove the

3. RESULTS AND DISCUSSION 3.1. Preparation and Characterization of Man-PEI CPs. The preparation of Man-PEI CPs was conveniently accomplished by a one-step process. Following the previously reported protocol,26 we synthesized Man-PEI CPs through

Figure 1. UV−vis absorption spectra of PEI, mannose, and Man-PEI CPs and fluorescence emission spectra of Man-PEI CPs. 1575

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Figure 2. SEM images of (a) PEI and (b) Man-PEI CPs.

Figure 5. (a) Agar plates of E. coli at a density of 3 × 104 treated with PEI and Man-PEI CPs for 3 h at 10 μg mL−1; plates were then incubated at 37 °C for 16 h. (b) Fluorescence microscope images of E. coli with PEI and Man-PEI CPs at 10 μg mL−1 stained by PI after sterilization for 3 h. Unstained cells indicate live bacteria while red staining indicates dead bacteria. Scale bar, 50 μm.

Figure 3. FT-IR spectra of (a) PEI, (b) mannose, and (c) Man-PEI CPs.

SEM was employed to characterize the morphological and structural characteristics of the obtained composite materials (Figure 2). Man-PEI CPs are monodisperse and exhibit rough spherical particles with a diameter of about 20 μm, which demonstrated that the copolymer particles were successfully prepared. To further verify the formation of a Schiff base between PEI and mannose, we utilized Fourier transform infrared (FT-IR) spectroscopy and 1H NMR spectroscopy to investigate. As shown in Figure 3, curves a, b, and c represent the FT-IR spectra of PEI, mannose, and Man-PEI CPs, respectively. The raw PEI has absorption peaks at 2942, 2831, and 1471 cm−1 corresponding to the stretching vibration and bending vibration of CH2 bonds, and characteristic absorptions at 3284 and 1577 cm−1 belong to the N−H bond. Compared to the spectrum of PEI and mannose, the bending vibration of the CO groups of mannose at 1597 cm−1 disappeared, and an obvious new peak at 1632 cm−1 was observed in the Man-PEI CPs spectrum, which can be attributed to the CN bond.26,31,32 In addition, the absorption bands at 3437 and 1385 cm−1 are associated with the stretching vibration and bending vibration of O−H, respectively, and the stretching vibration of C−O is located at 1084 cm−1, which reveals the presence of C−OH. In addition, the 1H NMR spectrum (Figure S1) of Man-PEI CPs has a new peak at 8.40 ppm belonging to H2CN protons,33 while PEI has no signal at this location. The results confirm the favorably synthesis of the Man-PEI CPs. 3.2. Evaluation of Antibacterial Activity. The molecular weight of PEI had a significant impact on the antibacterial activity,10 so the antibacterial activity of Man-PEI CPs prepared by PEI with different molecular weights was investigated. The

Figure 4. Sterilization rate of PEI and Man-PEI CPs at 10 μg mL−1 according to the number of E. coli colonies on agar plates.

facile nucleophilic addition chemistry between the primary amine on PEI and the aldehyde group on D-mannose. The Man-PEI CPs were soluble in aqueous solution without the need for further modification. The absorption spectra of ManPEI CPs, PEI, and mannose in water are respectively shown in Figure 1. It shows that the Man-PEI CPs solution has a new absorption peak at 352 nm, whereas PEI and mannose have nearly no absorption above 250 nm. On the other hand, ManPEI CPs display an intense fluorescence at 460 nm. The intrinsic fluorescence emission closely resembles that of PAMAM and methylated PEI.28−30 And the inset in Figure 1 displaying the optical property of Man-PEI CPs is faint yellow in daylight and bright blue fluorescent under an ultraviolet lamp (365 nm). 1576

DOI: 10.1021/acs.langmuir.7b03556 Langmuir 2018, 34, 1574−1580

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PEI was 600, the antibacterial activity increased significantly (Figure 5a). Therefore, PEI with a molecular weight of 600 was selected as a candidate for preparing Man-PEI CPs for the next experiment. In addition, we further conducted fluorescence imaging tests to prove the excellent bactericidal effect of Man-PEI CPs. After antibacterial experiments, PI was added to suspensions of E. coli with PEI and Man-PEI CPs for 15 min, which can specifically stain damaged or dead bacteria. Figure 5b shows the fluorescent images of E. coli suspensions and the merged images under phase contrast bright-field and the fluorescence field. After incubation with Man-PEI CPs, all cells emit red fluorescence that means that cells are killed, whereas less red fluorescence is observed when the bacterial cells are incubated with PEI. ManPEI CPs exhibited a higher efficient killing capability against bacteria than PEI at the same dosage concentration, implying that the antibacterial activity was obviously enhanced when PEI was modified with mannose. These results indicate that mannose played a vital role in the excellent bactericidal effect of Man-PEI CPs. In order to discuss the effect of mannose on the antibacterial activity, the antibacterial activity of Man-PEI CPs with different mass ratios (PEI/mannose) was evaluated by colony counting. As shown in Figure 6a, the sterilization rate of PEI (100:0 mg mL−1) was only 9.29 ± 2.27%. After grafting with mannose, the antibacterial activity increased as the amount of mannose increased. At a mass ratio of 100:36 mg mL−1, the sterilization rate was 99.45 ± 0.6%. These observations were further demonstrated by the agar plates of E. coli (Figure 6b). In comparison to the control plate, where a large number of E. coli colonies were observed, no colonies were found by treatment with Man-PEI CPs (100:36 mg mL−1). These clearly demonstrated that the outstanding bactericidal effect of ManPEI CPs is relevant to the high surface mannose ligand content. The phenol−sulfuric acid method34 was used to quantify sugars on PEI (seen in Tables S2 and S3). It can be seen from the result that the suitable surface-grafting degree of Man-PEI was achieved under the preferential molecular weight and mass ratio. The antibacterial performance of the antibacterial agent is usually determined by the minimum bactericidal concentration (MBC). The MBC is the minimum concentration of killing all bacteria with an antibacterial agent. It can be observed from Figure S2 that a 99.9% sterilization rate was recorded for E. coli K-12 with 220 μg mL−1 PEI, whereas the same sterilization rate could be readily obtained with 10 μg mL−1 Man-PEI CPs. Furthermore, the MBC of Man-PEI CPs was markedly lower than for some antibiotics and recently reported antibacterial polyethylenimine materials (Table S1). All of the above results indicate that the high antibacterial capability of Man-PEI CPs results from the presence of mannose. Therefore, we speculated that mannose was closely related to the adherence of PEI to the bacterial surface. 3.3. Mechanism of Antibacterial Activity. The majority of E. coli strains possess a lot of fimbriae with different structure and function, which can be mediated bacteria on the target cell adhesion and infection. Type I fimbriae is the most common fimbriae of E. coli, consisting of four different subunits of FimA, FimF, FimG, and FimH. It is well known that FimH is the determinant of the protein’s mannose-specific binding property; it possesses carbohydrate recognition sites, which produce a strong affinity for mannose.35−37 Therefore, it is assumed that the excellent bactericidal effect of Man-PEI CPs is relevant to

Figure 6. (a) Sterilization rate of 10 μg mL−1 Man-PEI CPs prepared by different mass ratios (PEI/mannose) according to the number of E. coli colonies on agar plates. (b) Agar plates of E. coli at a density of 3 × 104 treated with 10 μg mL−1 Man-PEI CPs for 3 h; plates were then incubated at 37 °C for 16 h.

Figure 7. Cell viability of PEI and Man-PEI CPs against HeLa cells at different concentrations for 24 h. The error bars represent the standard deviations of three parallel measurements.

antibacterial activity against Gram-negative bacteria, E. coli K12, was evaluated by colony counting. As shown in Figure 4, the antibacterial activity of PEI depended on its molecular weight. Increasing the molecular weight resulted in an increase in the antibacterial performance. The antibacterial activity of corresponding Man-PEI CPs was improved compared to that of unmodified PEI. Importantly, when the molecular weight of 1577

DOI: 10.1021/acs.langmuir.7b03556 Langmuir 2018, 34, 1574−1580

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Langmuir Scheme 1. Schematic Illustration of the PEI and Man-PEI CPs Antibacterial Strategy

base ligands are used in antibacterial and antifungal material.41,42 Similarly, the 1H NMR spectra (Figure S1) had confirmed the formation of the Schiff base between PEI and mannose that is conducive to the enhancement of antibacterial activity. 3.4. Cytotoxicity of PEI and Man-PEI CPs. The cell cytotoxicity of the PEI and Man-PEI CPs was tested using an MTT assay against HeLa cells. As shown in Figure 7, Man-PEI CPs do not exhibit obvious cytotoxicity under the antibacterial condition (10 μg mL−1). The cell viability remained at ∼75% after 24 h of incubation even if the concentration of Man-PEI CPs was increased to 500 μg mL−1. However, PEI exhibits certain cytotoxicity under the antibacterial condition (220 μg mL−1). The cell viability decreased to 56% at 500 μg mL−1 PEI. Therefore, the characteristic of low cell cytotoxicity indicates that Man-PEI CPs has great potential application as an antibacterial agent.

mannose, which improves the adherence of PEI on the bacterial surface. In our work, the Man-PEI CPs were incubated with E. coli for a fluorescence-based agglutination assay to determine if the mannose molecules attached to Man-PEI CPs retained their ability to bind with the FimH proteins of the pili in E. coli. From Figure S3, it can be shown that Man-PEI CPs can interact with the FimH proteins of the pili in E. coli by the better bacteria agglutination behavior. As a control experiment, PEI without mannose was also incubated with E. coli. PEI exhibited very little nonspecific binding to E. coli. These results show that the binding of Man-PEI CPs with E. coli is due to the interaction between the mannose and the FimH proteins rather than to nonspecific absorption to the Man-PEI CPs.38,39 The aldehyde group of mannose may consume the amino group of PEI and further reduce the nonspecific binding of Man-PEI CPs with E. coli. The enhancement of antibacterial ability can be attributed to the specific adherence of PEI on the surface of E. coli. To demonstrate the positive effect of mannose in Man-PEI CPs, we modified PEI with ascorbic acid to acquire AA-PEI CPs, which were selected as a model for conducting the control experiment. AA-PEI CPs could not specifically bind to E. coli because there is no specific recognition between ascorbic acid and E. coli. It can be seen from Figure S4 that AA-PEI CPs hardly had any antibacterial activity, whereas Man-PEI CPs exhibit an excellent bactericidal effect. In the meantime, the antibacterial activity of PEI and Man-PEI CPs against Grampositive bacteria, S. aureus, was studied at varying concentrations by colony counting. As shown in Figure S5, the activities of PEI and Man-PEI CPs against S. aureus were concentration-dependent. However, compared to unmodified PEI, the antibacterial activity of Man-PEI CPs did not exhibit any improvement. The major causes for this result are that Man-PEI CPs exhibits nonspecific binding to S. aureus. These observations demonstrated that the antibacterial ability of Man-PEI CPs mainly depends on the electrostatic action of positively charged PEI on the negative charge bacterial surface, which causes the destruction of the cell wall and the leakage of the cytoplasmic constituents, thereby leading to the death of bacteria.40 The enhancement of antibacterial ability is due to specific recognition between the mannose and FimH, which improves the specific adherence of PEI on the surface of E. coli. Moreover, previous studies had shown that the Schiff

4. CONCLUSIONS In this study, we have successfully modified PEI with mannose to construct Man-PEI CPs. By contrast with unmodified PEI, Man-PEI CPs possess low cytotoxicity and excellent antibacterial activity on E. coli by the specific recognition between FimH and mannose. Therefore, as an efficient antibacterial agent, Man-PEI CPs efficiently broaden the antibacterial spectrum of PEI. In addition, the synthesis of Man-PEI CPs is simple, rapid, and cost-efficient without complicated chemical modification. Given the above advantages, Man-PEI CPs provide promising applications for combating multiple bacteria and also can be used as a special agent for killing E. coli with low cytotoxicity.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.langmuir.7b03556. One table listing the antibacterial activity of antibiotics and PEI nanomaterials, 1H NMR spectra of PEI and Man-PEI CPs, the phenol−sulfuric acid method used to quantify sugars on PEI, the fluorescence-based bacterial aggregation assay, and the sterilization rate of PEI, ManPEI CPs, and AA-PEI CPs against E. coli and S. aureus (PDF) 1578

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AUTHOR INFORMATION

Corresponding Authors

*(M.L.) Phone: +86-29-85310517. Fax: +86-29-85310517. Email: [email protected]. *(B.L.) Phone: +86-29-81530726. Fax: +86-29-81530727. Email: [email protected]. ORCID

Mei Liu: 0000-0002-2547-1955 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (no. 21405101) and the Shaanxi Science and Technology Plan Projects (no. 2017NY-121).

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REFERENCES

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DOI: 10.1021/acs.langmuir.7b03556 Langmuir 2018, 34, 1574−1580