Dual-Recognition Förster Resonance Energy Transfer Based Platform

Article pubs.acs.org/ac

Dual-Recognition Förster Resonance Energy Transfer Based Platform for One-Step Sensitive Detection of Pathogenic Bacteria Using Fluorescent Vancomycin−Gold Nanoclusters and Aptamer−Gold Nanoparticles Mengqun Yu,† Hong Wang,† Fei Fu,† Linyao Li,† Jing Li,† Gan Li,† Yang Song,† Mark T. Swihart,‡ and Erqun Song*,† †

Key Laboratory of Luminescence and Real-Time Analytical Chemistry, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, People’s Republic of China ‡ Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, United States S Supporting Information *

ABSTRACT: The effective monitoring, identification, and quantification of pathogenic bacteria is essential for addressing serious public health issues. In this study, we present a universal and facile one-step strategy for sensitive and selective detection of pathogenic bacteria using a dual-molecular affinity-based Förster (fluorescence) resonance energy transfer (FRET) platform based on the recognition of bacterial cell walls by antibiotic and aptamer molecules, respectively. As a proof of concept, Vancomycin (Van) and a nucleic acid aptamer were employed in a model dualrecognition scheme for detecting Staphylococcus aureus (Staph. aureus). Within 30 min, by using Van-functionalized gold nanoclusters and aptamer-modified gold nanoparticles as the energy donor and acceptor, respectively, the FRET signal shows a linear variation with the concentration of Staph. aureus in the range from 20 to 108 cfu/mL with a detection limit of 10 cfu/mL. Other nontarget bacteria showed negative results, demonstrating the good specificity of the approach. When employed to assay Staph. aureus in real samples, the dual-recognition FRET strategy showed recoveries from 99.00% to the 109.75% with relative standard derivations (RSDs) less than 4%. This establishes a universal detection platform for sensitive, specific, and simple pathogenic bacteria detection, which could have great impact in the fields of food/public safety monitoring and infectious disease diagnosis.

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can be expensive and subject to poor reproducibility. The antibiotic- and lectin-based methods are simpler and much less expensive than antibody-based methods. However, their specificity is often unsatisfactory. Aptamer-based strategies can potentially provide simplicity and low cost in combination with acceptable selectivity, and have thus been of great recent interest.26−29 Förster (or fluorescence) resonance energy transfer (FRET) is a homogeneous signal transduction technique that is simple and rapid, sensitive, and selective.30−32 In this method, energy transfer from an energy donor to an energy acceptor occurs when a molecular recognition event brings the donor and acceptor into close proximity. This energy transfer produces a characteristic change in the fluorescence of the donor and/or acceptor. FRET has previously been employed for the

athogenic bacteria cause serious public health issues including food poisoning and infectious diseases, and can be used in biological weapons.1,2 Effective detection technology for pathogenic bacteria is vital to address these public health and security concerns. Therefore, the development of a sensitive, rapid, convenient, and low-cost method for specific detection of pathogenic bacteria is of great significance. Classic methods of detecting pathogenic bacteria, such as microorganism culture and polymerase chain reaction,3,4 are limited by the disadvantages of complicated operation or sample preparation, long analysis times, and low sensitivity and specificity. More recent methodologies for detecting pathogenic bacteria are based on various recognition molecules (e.g., antibodies,5−7 aptamers,8−16 antibiotics,17−20 lectins,21−23 phages,24,25 etc.) combined with signal transduction through fluorescence,6,9−11 resonance light scattering (RLS),8 electrochemical measurement,16,22 and surface-enhanced Raman scattering (SERS).14,15 Among the possible recognition strategies, antibody-based methods are simple and highly selective but rely on antibodies produced in animals, which © 2017 American Chemical Society

Received: December 13, 2016 Accepted: March 13, 2017 Published: March 13, 2017 4085

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determination of pathogenic bacteria using a combination of recognition molecules and nanomaterials.9,13 For example, Zuo et al. employed an organic dye-labeled aptamer as both recognition molecule and energy donor with graphene oxide as energy acceptor to achieve one-step, fast, and multiplexed pathogen detection in a microfluidic system.9 A similar approach to detection of bacteria using FRET was reported by Duan et al.13 In that study, the organic dye and graphene oxide was replaced by quantum dots (QDs) and carbon nanoparticles to achieve high quenching efficiency.13 Although the aforementioned strategies show promise, the fluorescent dye is subject to photobleaching, while QDs containing heavy metal cadmium ions raise toxicity and environmental concerns. Moreover, the detection strategies in these studies still involved complicated system or procedures. Gold nanoparticles (AuNPs), which are easily synthesized, showed good optical and colloidal stability and high extinction coefficient. These features make them an excellent choice as energy acceptor.33−36 Gold nanoclusters (AuNCs) with small size, good biocompatibility, and strong photobleaching-resistant photoluminescence, as well as easy synthesis, have great potential as an energy donor.37−42 On the basis of the broadspectrum and specific recognition capabilities of antibiotic and aptamer molecules, we have previously demonstrated specific and sensitive quantification of bacteria through a dualrecognition strategy combining antibiotic and aptamer recognition moieties.43 However, the detection strategy in that study involved several steps (incubation, magnetic enrichment, elution, and fluorescence detection). Here, building on that work, we demonstrate a novel antibiotic and aptamer dual-molecule affinity-based FRET strategy for facile and sensitive detection pathogenic bacteria in a single step. To demonstrate the feasibility of this strategy, a proof-of-concept method for Gram-positive (G+) bacterium of Staphylococcus aureus (Staph. aureus) assay was designed, in which vancomycin-functionalized AuNCs (Van−AuNCs) and aptamer-modified AuNPs (aptamer−AuNPs) were employed as energy donor and acceptor, respectively (Scheme 1). On the

Article

EXPERIMENTAL SECTION

Materials and Apparatus. Vancomycin hydrochloride (Van) was purchased from Amresco LLC; chloroauric acid (HAuCl4) was provided by Sinopharm Chemical Reagent Co. Ltd.; tris(2-carboxyethyl)phosphine (TCEP) was purchased from Pierce Chemical (Rockford, IL, U.S.A.). Staph. aureus (ATCC 29213) was obtained from China General Microbiological Culture Collection Center. Bacillus subtilis (B. subtilis, CCTCCAB 90008), Sarcina lutea (Sar. lutea, CCTCC AB 91100), Escherichia coli (E. coli, CCTCC AB 212355), Salmonella typhimurium (Sal. typhimurium, CCTCC AB 91105), and Pseudomonas aeruginosa (P. aeruginosa, CCTCC AB 93078) were obtained from China Center for Type Culture Collection. The Staph. aureus aptamer and random DNA sequence (sequence information shown in Table S-1 in Supporting Information) were synthesized by Sangon Biological Science and Technology Company (Shanghai, China). Human serum was supplied by Department of Oncology, the Ninth People’s Hospital of Chongqing (China). The ultrapure water used in the experiments was prepared using a Milli-Q system (Merck Millipore, U.S.A.) and had a resistivity of 18.2 MΩ cm. UV−vis absorption spectra were recorded on a Shimadzu UV-2450 spectrophotometer. Fluorescence spectra were obtained using a fluorescence spectrophotometer (F-7000, Hitachi), and fluorescence images were recorded using an inverted fluorescence microscope (Olympus IX71) or a confocal laser scanning microscopy (IX2-DSU, Olympus, Japan). The ζ-potential was measured using a Malvern Zetasizer Nano ZS ZEN3600 instrument (Malvern Instruments, United Kingdom). Morphology was characterized using a transmission electron microscope (TEM) (LIBRA 200PE, Carl Zeiss SMT). Bacteria Culture and Counting. Bacteria were grown in Luria−Bertani broth medium at 37 °C with continuous shaking overnight and then washed with PBS by centrifugation (3500 rpm/5 min). According to the conventional agar plate-counting method, after incubation at 37 °C for 18 h, the colonies on the plates were counted to determine the number of colonyforming units per milliliter (cfu/mL), yielding the concentration of ∼109 cfu/mL. Detection of Staph. aureus using the DRU-FRET Strategy. First, Van−AuNCs (0.2 mg/mL) were mixed with aptamer−AuNPs (2.5 nM). Then Staph. aureus with different amounts (0, 10, 20, 30, 102, 103, 104, 105, 106, 107, 5 × 107, and 108 cfu/mL, respectively) was added into the above solution and incubated at 37 °C for 30 min in binding buffer. The fluorescence intensity of the final mixture was measured directly by fluorescence spectrophotometer at λex/λem = 303/412 nm. The same procedures were employed with a random DNA sequence (RanSeq) and with nontarget bacteria (such as B. subtilis, Sar. lutea, E. coli, Sal. typhimurium, and P. aeruginosa) that were supplied in the control groups. Detection of Staph. aureus from Confounding Bacteria Mixed Samples. Varying concentrations of Staph. aureus were mixed with B. subtilis, Sar. lutea, E. coli, Sal. typhimurium, and P. aeruginosa (each at 1 × 108 cfu/mL) to construct an artificial complex specimen. The mixtures were then subjected to the assay as described above. Detection of Staph. aureus in Real Samples. The qualified milk and orange juice samples were purchased from local supermarket. Human serum was obtained from healthy

Scheme 1. Illustration of the Vancomycin and Aptamer Dual-Recognition Molecule Based FRET Assay Platform for Staph. aureus

basis of this strategy, Staph. aureus could be detected within 30 min with good linear range, detection limit, and reliability for authentic samples. The Van−AuNCs and aptamer−AuNPs dual-recognition units based FRET strategy (DRU-FRET) can serve as a universal detection platform for sensitive, specific, rapid, simple, and cost-efficient testing for pathogenic bacteria, which in turn could have great impact in the fields of public safety, public health, and infectious disease diagnosis. 4086

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Analytical Chemistry volunteers. Staph. aureus was added at known concentration to 10-fold diluted milk, 5-fold diluted orange juice, and human serum to evaluate the applicability of the proposed strategy to real samples.

After the Van−AuNCs and aptamer−AuNPs were prepared and characterized, respectively (Figures S-1 and S-3), they were mixed with the target Staph. aureus and then subjected to fluorescence measurement (shown in Figure 2). As shown in Figure 2A, compared with the blank sample (mixture of Van− AuNCs with aptamer−AuNPs dispersed in buffer), the fluorescence intensity of the mixture with Staph. aureus showed a modest decrease in intensity with fluorescence quenching efficiency about 12% (the fluorescence quenching efficiency of η was calculated by the equation η = (F0 − F)/F0 × 100%, where F0 and F are the fluorescence intensities of the detection system in the absence and presence of Staph. aureus or other bacteria). However, when the aptamer was replaced with a random DNA sequence (RanSeq) or when Staph. aureus was replaced with nontarget bacteria of E. coli (Gram-negative bacterium, G−) and Sar. lutea (G+), nearly a slight fluorescence intensity decrease was observed, with corresponding η values of 3.08%, 1.14%, and 2.81%, respectively. The fluorescence intensity changes ΔF (ΔF = F0 − F) for all the bacteria samples compared with the blank (without bacteria) are summarized with a bar graph for more clear understanding (the inset in Figure 2A). And the fluorescence quenching phenomenon for the target Staph. aureus was visually observed under a fluorescence microscope. As shown in Figure 2B, the fluorescence image d shows subdued blue fluorescence dots (pointed out by red circles for easy view) around the site the Staph. aureus located (c) when they were treated with Van− AuNCs/aptamer−AuNPs mixture together. On the contrary, we could see bright blue fluorescence dots (b and f) on the same sites of where the Staph. aureus located (a and e) when they were incubated with Van−AuNCs (a and b) only or a mixture of Van−AuNCs and RanSeq−AuNPs (e and f). Optimization of Detection Conditions. To obtain the best sensing performance, the dosages of Van−AuNCs and aptamer−AuNPs and the incubation time were optimized using the fluorescence intensity as the evaluating index through the orthogonal experiment method employing the L9(33) orthogonal layout.44−46 Each of three major factors (dosages of Van−

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RESULTS AND DISCUSSION Principle of Van−AuNC and Aptamer−AuNP Based DRU-FRET Strategy for Detecting Staph. aureus. The Van−AuNC and aptamer−AuNP based DRU-FRET strategy for Staph. aureus is illustrated in Scheme 1. The approach was designed based on the following features. First, the Van and aptamer molecules exhibit broad-spectrum and highly specific binding, respectively, on the surface of Staph. aureus (Figure S2). This provides an opportunity to construct the FRET platform on the surface of bacteria. Second, the Van−AuNCs show bright blue fluorescence while maintaining their antibiotic activity for Staph. aureus (Figure S-2). Third, the emission spectrum of Van−AuNCs shows spectral overlap with the absorbance spectrum of aptamer−AuNPs (Figure 1), suggesting that the aptamer−AuNPs can serve as an energy acceptor for Van−AuNCs.

Figure 1. Typical emission spectrum of Van−AuNCs and the absorbance spectrum of aptamer−AuNPs. The inset shows a photograph of Van−AuNCs under 365 nm light illumination.

Figure 2. (A) Fluorescence spectra of the Van−AuNCs before and after mixing with aptamer−AuNPs, bacteria, or both of them. The inset is a bar graph of fluorescence intensity changes ΔF for different samples in panel A. (B) Fluorescence microscope images of Staph. aureus after incubation with Van−AuNCs only (a and b), with the mixture of Van−AuNCs and aptamer−AuNPs (c and d), and with the mixture of Van−AuNCs and RanSeq−AuNPs (e and f) simultaneously. The blue fluorescence dots in the fluorescence image are pointed out by red circles. 4087

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Figure 3. (A) Fluorescence spectra of the DRU-FRET biosensor in the presence of Staph. aureus at varying concentrations (curves a−l correspond to 0, 10, 20, 30, 102, 103, 104, 105, 106, 107, 5 × 107, and 108 cfu/mL, respectively). (B) The calibration curve obtained from the spectra of panel A showing the linear dependence of change in fluorescence intensity on the logarithm of Staph. aureus concentration (log10N cfu/mL).

AuNCs and aptamer−AuNPs and the incubation time) was studied at three levels (shown in Table S-2). The orthogonal experiment program, results, and analysis are shown in detail in Supporting Information (Tables S-3 and S-4). As shown in Table S-4, the fluorescence intensity change of ΔF (ΔF = F0 − F, where F0 and F are the fluorescence intensities in the absence and presence of Staph. aureus with concentration at 108 cfu/ mL) reached a maximum when the dosages of Van−AuNCs and aptamer−AuNPs were 0.2 mg/mL and 5 nM, respectively. Using these optimal dosages, the fluorescence intensity change of the system reached equilibrium after 30 min. Quantitative Detection of Staph. aureus Based on the DRU-FRET Strategy. After the assay conditions were optimized, the linear range and detection limit of Staph. aureus by the DRU-FRET strategy were studied. Specifically, a series of Staph. aureus solutions of different concentrations (0, 10, 20, 30, 102, 103, 104, 105, 106, 107, 5 × 107, and 108 cfu/mL, respectively) were incubated with Van−AuNCs and aptamer− AuNPs simultaneously for 30 min, followed by the determination of the fluorescence intensity of each sample. As shown in Figure 3, the decrease in fluorescence intensity (ΔF) of the mixture with Staph. aureus was linearly dependent upon the logarithm of the concentration of Staph. aureus from 20 to 108 cfu/mL with a detection limit of 10 cfu/mL (ΔF = 109.92 log10N − 96.09, R = 0.9866, where N stands for the quantity of Staph. aureus in cfu/mL; limit of detection (LOD) was determined by the equation LOD = 3S/K, where S was the standard deviation of the blank samples (n = 10) and K is the slope of the calibration curve). Selectivity of the DRU-FRET Strategy for Staph. aureus. In the environment, Staph. aureus may be usually accompanied by other bacteria, including both G+ and G− bacteria; therefore, the selectivity of the DRU-FRET strategy for Staph. aureus should be confirmed. The selectivity of the DRU-FRET strategy for Staph. aureus was tested by comparing the fluorescence intensity change of the detecting system to the Staph. aureus and other interfering bacteria. Each of the five interfering bacteria [B. subtilis (G+), Sar. lutea (G+), E. coli (G−), Sal. typhimurium (G−), and P. aeruginosa (G−) all at 1.0 × 108 cfu/mL], a mixture 1 of the five interfering bacteria together, and another mixture 2 (containing Staph. aureus and five interfering bacteria all at 1.0 × 108 cfu/mL) were assayed with the proposed method, respectively, and all the obtained fluorescence signals were compared with that from blank sample (only PBS buffer without any bacteria). As shown in Figure 4, compared with the Staph. aureus and blank sample,

Figure 4. Fluorescence response (ΔF) for blank buffer, Staph. aureus, interfering bacteria, and the mixtures of them, respectively. The concentration of Staph. aureus is 105 cfu/mL, and the five interfering bacteria are all at 108 cfu/mL.

the fluorescence responses from the interfering bacteria were less than 8% of that from the former and no more than 4 times of that from the latter. Specifically, the degree of interference (DI) of these interfering bacteria to the target Staph. aureus was evaluated according to the following equation: DI = (FR I − FR B)/(FR S − FR B) × 100%

(1)

where FRI, FRS, and FRB are the fluorescence responses from the interfering bacteria, Staph. aureus, and the blank sample, respectively. The DI values of B. subtilis, Sar. lutea, E. coli, Sal. typhimurium, P. aeruginosa, and mixture 1 were calculated to be 4.11%, 6.35%, 2.49%, 3.77%, 3.00%, and 6.95%, respectively, implying negligible interference of these bacteria. The fluorescence response of mixture 2 only showed a small change of 1.43% in comparison with that of the Staph. aureus sample. The above results revealed satisfactory selectivity of the proposed DRU-FRET strategy for Staph. aureus detection. Detection of Staph. aureus in Authentic Samples. In order to demonstrate the applicability of the DRU-FRET strategy for Staph. aureus detection in real samples, several test samples (qualified milk and orange juice samples and human serum from healthy volunteers) spiked with Staph. aureus were analyzed. Before assay, the interference (that means the background signals produced by the pure real sample without spiking any Staph. aureus) of the real sample to the proposed DRU-FRET strategy was studied. As shown in Figure S-4, the 4088

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Analytical Chemistry Table 1. Recovery Efficiency of Staph. aureus Detected in Real Samples Based on the Proposed DRU-FRET Strategy samples

added (log10N cfu/mL)

measd (log10N cfu/mL)

recovery (%)

RSD (%, n = 3)

milk 1 milk 2 milk 3 orange juice 1 orange juice 2 orange juice 3 human serum 1 human serum 2 human serum 3

2 4 6 2 4 6 2 4 6

2.01 4.39 6.35 1.98 4.07 6.06 1.98 4.01 5.98

100.50 109.75 105.83 99.00 101.75 101.00 99.00 100.25 99.67

2.46 0.98 2.08 3.33 1.71 3.07 2.89 1.17 1.35

milk sample with 10-fold dilution and another two sample (juice and serum) with 5-fold dilution produced comparable background signals with the blank sample (PBS buffer). Then the diluted real samples spiked with Staph. aureus were subjected to assay with the DRU-FRET strategy. The results in Table 1 show that the recoveries varied from 99.00% to 109.75% with variation coefficients of 0.98−3.07%, indicating that the proposed method could be applied for detection of Staph. aureus in authentic samples. The limit of detections in the diluted milk, orange juice, and human serum sample for Staph. aureus are 300, 100, and 100 cfu/mL, respectively. Although the predilution of real sample is required for Staph. aureus assay, fortunately the dilution operation is very simple and fast, which will not badly affect the efficiency of the whole DRU-FRET strategy based assay. A brief comparison of various surface bioaffinity sensing methods for detecting of Staph. aureus is summarized in Table S-5. Compared with other bioaffinity sensing methods reported, the as-proposed strategy in this study is preferable for Staph. aureus assay due to its high sensitivity, wide analytical range (covering several orders of magnitude), simpleness (one-step assay with an ordinary instrument), and rapidness (30 min). Compared with our previously published work,43 the DRUFRET strategy for Staph. aureus proposed in this study is much simpler and faster, and it shows better detection ability with lower LOD of 10 cfu/mL for Staph. aureus in blank buffer. As for its disadvantage, due to the lack of preseparation for the target bacteria from other interfering components in the real sample before the fluorescence measurement, as was done in our previous work,43 the DRU-FRET strategy here showed some interference background signals for the original real sample (as shown in Figure S-4), resulting in a predilution step to the real sample. Another point is that the emission peak of the donor (Van−AuNCs) did not fully overlap with the absorbance peak of the acceptor (aptamer−AuNPs) (Figure 1), resulting in relatively lower fluorescence quenching efficiency (ηmax < 21%, Figure 3) in this study. Fortunately, the background signal of such measurement is very small based on the data, making the practical measurement still feasible. Therefore, a further work referring to prepare a new FRET sensor based on antibiotics-modified fluorescence nanoclusters or aptamer-modified QDs (as donor) with the emission peak overlapping mostly with the absorbance peak of the acceptor (aptamer−AuNPs or antibiotic-AuNPs) should be ongoing to improve the fluorescence quenching efficiency and sensitivity.

the fluorescent Van−AuNCs (as energy donor) and aptamer− AuNPs (as energy acceptor). With this strategy, pathogenic Staph. aureus could be specifically detected within 30 min over a range from 20 to 108 cfu/mL with a detection limit of 10 cfu/ mL in one step. Staph. aureus spiked in authentic samples was also quantified with good recoveries. Compared with previously reported Staph. aureus assays, the strategy demonstrated here is simple and rapid, while providing both a wide detection range and ideal sensitivity and selectivity. Moreover, the method described herein for Staph. aureus assay is only a proof-ofconcept work, and this concept of dual-recognition moleculebased FRET strategy could be expanded to other pathogenic bacteria detection or simultaneous multiple bacteria detection by simply changing the molecules specific to the desired target, demonstrating a universal platform for bacterial assay.

CONCLUSION In summary, we have developed a facile, rapid, and reliable onestep strategy for sensitive and selective detection of Staph. aureus using a dual-recognition unit FRET platform based on

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21575118, 21477098), the Science and Technology Talent Cultivation Project of Chongqing

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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.analchem.6b04958. Information on DNA sequence and modification, synthesis protocol and bioactivity characterization of Van−AuNCs, preparation and characterization of aptamer−AuNPs, optimization of detection conditions for Staph. aureus, and the interference of the pure real sample without spiking any Staph. aureus to the proposed DRU-FRET strategy (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Fax: +862368251225. Tel: +862368251225. E-mail: eqsong@ swu.edu.cn. ORCID

Yang Song: 0000-0001-7716-9216 Mark T. Swihart: 0000-0002-9652-687X Erqun Song: 0000-0003-4026-090X Author Contributions

The manuscript was written through contributions of all authors. Notes

The authors declare no competing financial interest.

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(cstc2014kjrc-qnrc00001), and funding support from the Beijing National Laboratory for Molecular Sciences (BNLMS).

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DOI: 10.1021/acs.analchem.6b04958 Anal. Chem. 2017, 89, 4085−4090