âEnd-Onlyâ Functionalized Oligo(phenylene ethynylene)s: Synthesis

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“End-Only” Functionalized Oligo(phenylene ethynylene)s: Synthesis, Photophysical and Biocidal Activity Zhijun Zhou,†,‡ Thomas S. Corbitt,† Anand Parthasarathy,§ Yanli Tang,† Linnea K. Ista,† Kirk S. Schanze,§ and David G. Whitten*,† †

Department of Chemical and Nuclear Engineering, Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico 87131-1341, United States, ‡Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-1341, United States, and §Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United States

ABSTRACT It is essential to develop alternative strategies to treat infections, especially those infections caused by Staphylococcus aureus, which is responsible for most skin infections. Among those strategies, light-induced inactivation of pathogens appears to be a promising candidate. We present four novel “end only” oligo(phenylene ethynylene)s (EO-OPE-1s) that have the ends functionalized with cationic groups and are powerful light-activated biocides against Escherichia coli, Staphylococcus epidermidis, and S. aureus. We have correlated the light-induced biocidal activities with singlet oxygen quantum yields Φ (1O2) of EO-OPE-1s, and a higher Φ (1O2) correlates with a better light-induced biocidal activity. Coupled with our previous work on the interactions of EO-OPE-1s with dioleoyl-sn-glycero-3-phosphocholine (DOPC)/cholesterol vesicles, we believe the biocidal process involves the following: (1) EO-OPE-1s penetrate the bacterial membrane, (2) EO-OPE-1s photosensitize the generation of singlet oxygen and/or other reactive oxygen species, and (3) singlet oxygen and/or reactive oxygen species trigger the cytotoxicity. SECTION Biophysical Chemistry

been tested as biocides.9-11 Among potential photosensitizers, poly(phenylene ethynylene) (PPE) derivatives have attracted intense research interest in recent years because of their interesting photophysical and photochemical properties.12 However, the antimicrobial activity of this series of polymers has not yet been explored extensively.13-15 Our previous work has demonstrated that several PPEs with pendant quaternary ammonium groups are effective light-activated biocides, which inhibit the growth of Gram-positive spores and Gram-negative bacteria such as Escherichia coli.16-19 Moreover, it has been shown that there is a strong correlation between activity and oxygen availability.16,19-21 To explore the correlation of structure and reactivity, we have synthesized “end only” oligo(phenylene ethynylene)s (EO-OPE-1s) with remarkable light-inducible biocidal activity by functionalizing the ends with cationic groups.22 In this manuscript, we present A, B, and C (Figure 1) with two net positive charges, which are quaternary ammonium salts without pendant groups attached to the middle aromatic ring, and anionic D (Figure 1). These oligomers kill Gram-negative bacteria such as E. coli and Gram-positive bacteria such as Staphylococcus epidermidis and S. aureus under 365 nm radiation with the effect being C > A > B > D. Notably, C effects 100% killing against

B

acterial infections in healthcare settings, such as in implanted devices, have become a global issue, and the resistance to many antibiotics used in treatment for pathogenic infections makes this problem even more serious. It becomes essential to develop alternative strategies to treat infections, especially those infections caused by Staphylococcus aureus, which is responsible for most skin infections.1,2 Among those strategies, light-induced inactivation of pathogens appears to be a promising candidate.3 The photoinactivation reaction has been well documented, and the process is believed to involve three steps:4 (1) A photosensitizer is excited from the ground state S0 to its excited singlet state S1; (2) S1 decays to a lower energy but longer lived triplet state S3 via intersystem crossing (ISC), which in turn transfers its energy to molecular triplet oxygen to generate reactive oxygen species (ROS, type I photo reaction) or to generate singlet oxygen (1O2, type II photo reaction); (3) ROS or 1O2 may further oxidize a variety of biological substrates locally, such as lipids, proteins, nucleic acids, and other unsaturated components, which can lead to many consequences, ultimately causing irreversible cellular damage and cell death. However, it is still not clear which ROS plays the major role; nevertheless, much evidence has shown that singlet oxygen plays a pivotal role in the process.5-8 The development of photosensitizers providing high-efficiency, broad-spectrum, and controllable release antimicrobials plays a key role. Various classes of chemicals, such as porphyrins, C60 derivatives, phthalocyanines, and gold nanoparticles have

r 2010 American Chemical Society

Received Date: August 3, 2010 Accepted Date: October 14, 2010 Published on Web Date: October 21, 2010

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DOI: 10.1021/jz101088k |J. Phys. Chem. Lett. 2010, 1, 3207–3212

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Transient absorption experiments were carried out for the oligomers in methanol and water. Near UV excitation (λ = 355 nm, 5 ns pulse) of each oligomer produces a long-lived transient absorption extending throughout the visible region (see Figure S11 and other Supporting Information). A summary of the transient absorption spectral features and decay kinetics is provided in Table 1. In each case, the transient has a lifetime in the 1-4 μs range, and it is efficiently quenched by O2, suggesting assignment to the triplet excited state (TT absorption). Several attempts were made to use the energy transfer method to determine the triplet yields, but these experiments were not successful. However, inspection of the initial amplitude of the TTabsorption immediately following the laser pulse (ΔA, t = 0, Table 1) reveals that the TTabsorption of C is substantially larger than for the other oligomers, suggesting a higher triplet yield. This qualitative result is consistent with the fluorescence data in suggesting that the triplet yield is enhanced by the thienylene unit in C. Having established that the triplet state is produced by direct excitation of the oligomers, we determined their ability to sensitize singlet oxygen in deuterated methanol; the singlet oxygen quantum yields (ΦΔ) are listed in Table 1. All of the oligomers sensitize singlet oxygen, as evidenced by the observation of emission at 1260 nm. Interestingly, the observed singlet oxygen quantum yields vary in the sequence C . A ∼ B > D. Note that this sequence runs parallel to the relative triplet yields as inferred from fluorescence and transient absorption results. In summary, all the oligomers sensitize 1O2 upon near-UVexcitation. Among them, the thiophene derivative C is the most efficient singlet oxygen sensitizer with ΦΔ ∼ 45%. The higher efficiency for singlet oxygen production in C is the result of an enhanced ISC yield, which is likely due to spin-orbit coupling induced by the thienylene sulfur. Biocidal Studies. The biocidal activities of the EO-OPE-1s containing cationic quaternary ammonium groups when exposed to 365 nm radiation in a photoreactor were evaluated against E. coli, S. epidermidis, and S. aureus. After exposure for 30 min to 365 nm UV radiation, significant kills of each bacteria occurred at very low concentrations of EO-OPE-1s (Figure 2 and Figures S1 and S2), while higher concentrations were needed for dark killing (Figures S3-S5). The most pronounced kills were seen for C in the light, which is different from a structurally analogous thiophene-substituted PPE-type polymer, which is effective at dark killing but has very little light-activated killing.21 In the thiophene-substituted PPE system, the polymer is highly aggregated in aqueous solution, which causes (1) less contact with bacteria and (2) fluorescence quenching; hence, the light-activated biocidal activity is attenuated. Small molecules such as C are less prone to aggregation, increasing the potential for cytoplasmic membrane penetration; hence, it is not surprising to see a strong biocidal activity. We also noticed A was more efficient for killing bacteria in light than B, even though the two oligomers have very similar ΦΔ (Table 1); this effect might be attributed to aggregation of B in aqueous solution due to its lower solubility. Anionic oligomer D exhibits lower biocidal activity toward E. coli and S. aureus (Figure 2 and Figure S2), even though it has a very similar triplet yield to cationic oligomers A and B. This phenomenon may be due to

Figure 1. Structures of EO-OPE-1s. A, B, and C are cationic molecules, while compound D is an anionic molecule.

S. aureus at concentrations as low as 10 ng/mL after a half hour irradiation (Figure S2, Supporting Information), which is quite efficient in comparison to other disinfectants.23-25 Absorption and Fluorescence. Each of the oligomers absorbs light strongly in the near-UV region as shown by the spectra in Figure S10. Careful studies of the absorption behavior of the oligomers in solution reveals trends in solubility. In particular, given that there are only two hydrophilic groups attached on both ends of EO-OPE-1s through a large hydrophobic aromatic segment, these compounds are poorly soluble in water, moderately soluble in CH3OH, but quite soluble in dimethylformamide (DMF) and DMSO. Time-dependent studies indicate that absorbance intensity measured immediately (1 min) after solution preparation for A and C (10 μM in H2O) is the same as that measured 30 min later; in contrast, the intensity of B is enhanced around 2 times over 30 min, and D is enhanced 1.5 times (Figure S10). This indicates that B and D dissolve in water more slowly than the other EO-OPE-1s. Photophysics and Singlet Oxygen Generation. In order to understand the mechanism by which oligo(phenylene ethynylene) derivatives A-D function as light-activated biocidal agents, a complete study of their photophysics was carried out in methanol and water. The photophysical data of A-D in methanol are consolidated in Table 1 (data obtained in water solution are in the Supporting Information, Table S1). A closer look at the results presented in Table 1 reveals several clear trends. First, all of the oligomers absorb in the near-UV region; however, the absorption of C, which contains a thienylene unit, is slightly red-shifted. Fluorescence was observed for all of the oligomers in the near-UV region, and, in parallel with the absorption result, the emission from C is also red-shifted. Interestingly, the fluorescence quantum yield (ΦF) is relatively high for the phenylene oligomers (A, B, and D), whereas it is significantly lower for C (ΦF for C is ∼6 times less than that of A and B). A similar trend is seen in the fluorescence decay data, where the lifetime (τF) of C is less than that of the other oligomers. Taken together, these data suggest that there is an accelerated singlet decay pathway operating in C. As suggested by the data discussed below, we believe that singlet decay is more rapid in C because the rate of ISC to the triplet state is enhanced.


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Table 1. Photophysical Data for Compounds A-D in Methanol Solution parameter

solvent

A

B

C

D

λmax (absorption/nm)

MeOH

326

328

355

λmax (fluorescence/nm)

MeOH

355

358

390

360

ΦFa

MeOH

0.73 ( 0.03

0.69 ( 0.03

0.12 ( 0.01

0.53 ( 0.02

ΦΔb τF/ns

CD3OD MeOH

0.20 ( 0.02 0.4

0.17 ( 0.03 0.45

0.45 ( 0.03 0.23

0.09 ( 0.02 0.52 (97%)

327

2 (3%) TTAbs (λ/nm)

MeOH

598

603

506

547

TTAbs (ΔA, t = 0)

MeOH

0.28

0.26

0.37

0.07

τtriplet (μs)

MeOH

2.8

2.3

1.6

3.7 0

Measured using quinine sulfate in 0.1 M sulfuric acid (ΦF = 0.54) as an actinometer. Measured in CD3OD using 2 -acetonaphthone (ΦΔ = 0.79) as an actinometer. a

b

Figure 2. The graph of A, B, C, and D against E.coli with irradiation over 30 and 60 min. X axis: (i) concentration of each compound (μg/mL), (ii) time (min), (iii) compound, and (iv) dead percentage (%).

the Coulombic repulsion between anionic D and bacteria, which hinders D approaching and/or binding to bacteria. To investigate the dose-dependent and time-dependent effects, various concentrations of each EO-OPE-1 were tested over 0, 30, and 60 min. The results show that higher concentration causes similar or more killing (Figure 2 and Figures S1 and S2). We previously reported that “inner filter” effects existed in polymer systems at high concentrations,27 but this effect was not observed in the present study. This is likely due to the low-dose response of the bacteria to the EO-OPE-1s. Moreover, oligomer-based biocides are much more active against Gram-positive bacteria than Gram-negative bacteria, although their antibacterial activities against Gram-negative are excellent in light too. This phenomenon can be attributed to differences in the membrane structure. On the other hand, the time-dependent biocidal activity investigation suggests that more kills will be obtained over time. The oligomers presented herein show dramatic lightinduced biocidal activity. To the best of our knowledge, this is the first study that demonstrates light-induced biocidal activity of phenylene ethynylene oligomers. The light-induced biocidal activity is correlated with the relative triplet yields of the EO-OPE-1s, and the results suggest that a higher triplet


yield affords better light-induced biocidal activity. Anionic molecule D exhibits relatively poor light-induced biocidal activity due to Coulombic repulsion, which probably results in little or no attachment of D to the surface or insertion into the membrane. We also found that hydrophobic nature of EO-OPE-1s series plays an important role in the biocidal activity, which is consistent with the reported results with nucleic acid stain.28,29 Since our previous work about the interactions of EO-OPE-1s with dioleoyl-sn-glycero-3-phosphocholine (DOPC)/cholesterol vesicles demonstrated that EO-OPE-1s insert into the vesicle bilayer inducing leakage,30 we believe the biocidal process involves the following: (1) EO-OPE-1s penetrate the bacterial membrane, (2) EO-OPE-1s photosensitize the generation of singlet oxygen and/or other ROS, and (3) singlet oxygen and/or ROS trigger the cytotoxicity. Materials. A, B, C, D, and all synthetic intermediates were synthesized through multistep reactions. 2,5-Diiodothiophene, ethynyl(trimethyl)silane, 2,2-dioxide-3-chloro-N,N-dimethylpropan-1-amine, CuI, K2CO3, diisopropylamine, potassium biocarbonate, Pd(PPh3)2Cl2, 2-chloro-N,N-dimethyl-ethanamine, oxathiolane, and 4-iodophenol-1,4-diiodobenzene were purchased from Sigma-Aldrich (St. Louis, MO) and used as received. All of the solvents were HPLC grade purchased from Honeywell

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Scheme 1. The Synthesis of A, B, C, and Da

a (a) Trimethylsilyl acetylene, Pd(PPh3)2Cl2, CuI, diisopropylamine, CHCl3, (b) K2CO3, CH3OH, CH2Cl2, (c) KOH, DMSO, 3-chloro-N,N-dimethylpropan-1-amine, (d) 2-chloro-N,N-dimethyl-ethanamine, (e) NaOH, dioxane, H2O, oxathiolane, (f) Pd(PPh3)2Cl2, CuI, diisopropylamine, CHCl3, (g) Pd(PPh3)2Cl2, CuI, H2O, diisopropylamine, (h) CH3I, CH2Cl2.

(Morristown, NJ) and used without purification. The stains, Syto 9, Syto 24, and propidium iodide were obtained from Molecular Probes, Inc. (Eugene, OR). Synthesis. Synthesis of these molecules is straightforward, requiring up to five steps (Scheme 1) in each case. however, yields (purification by column chromatography) for the steps involving the conversion of compounds 5 to 8, 5 to 9, and 6 to 10 are low (see Supporting Information). This may be caused by poor solubility in eluants and high affinity for silica gel of 8, 10, and their intermediates such that the majority of the product is absorbed on the silica gel. In addition, the instability of compound 4 may be responsible for the low yield of the conversion of 5 to 9. Target molecules are easily characterized by NMR (proton and carbon) and mass spectroscopy. Photophysical Studies. For the absorption and fluorescence spectroscopy, a stock solution of each oligomer was prepared with a concentration of 1 mM in 10% v/v solution of dimethyl sulfoxide (DMSO) and H2O. A 30 μL aliquot of the stock solution of each EO-OPE-1 was diluted into 3 mL aqueous solution in a quartz cuvette to give a concentration of 10 μM. Absorption and fluorescence were performed on a plate reader (SpectroMax M-5 microplate reader, Molecular Devices) at 24 °C. Transient absorption spectra were recorded for EO-OPE-1 samples both in methanol and water. The transient absorption systems are described elsewhere.17,26 The optical density was adjusted to ∼0.7 at the excitation wavelength (355 nm) with the laser fluence being 6-7 mJ cm-2.


Solutions were purged with argon for 45 min before making transient absorption spectroscopy measurements. Biocidal Studies and Dead/Live Assay. All items that contacted bacteria were sterile before use. E. coli, S. epidermidis, and S. aureus were cultured in 50 mL of Difco nutrient broth (Becton, Dickinson and Company, Sparks, MD, USA), and BBL Brain Heart Infusion (Becton, Dickinson and Company), respectively, for 18 h at 37 °C under shaking. The bacteria were collected by centrifuging 50 mL of culture at 4000 rpm in an Eppendorf centrifuge for 15 min at 4 °C. The pellet was resuspended with the assistance of vortex in 25 mL of 0.85% NaCl solution and repelleted. The wash cycle was repeated twice. Bacterial concentrations were measured and normalized using a disposable hemocytometer (INCYTO Co., Ltd.), counts being 2.5-3.0 107/mL. The diluted bacteria suspension was added to 1.5 mL of opaque or transparent microtubes with aliquots of 500 μL. Three groups of live controls were prepared with bacteria suspension in opaque microtubes, transparent microtubes, and quartz cuvettes at the same concentrations. These bacteria samples were titrated by EO-OPE-1 aqueous solutions with various concentrations followed by remaining in the dark for dark samples/controls and exposing to UV 365 nm radiation in a photoreactor chamber (LZC-ORG, Luzchem Research Inc.) for light samples/controls with certain duration. Live/dead assays were carried out using two sets of stains: SYTO 9/propidium iodide for E. coli and SYTO 24/propidium

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iodide for S. epidermidis and S. aureus. SYTO 9 and SYTO 24 are cell membrane permeant nucleic acid stains with green (∼498 nm for SYTO 9 and ∼515 nm for SYTO 24) fluorescence and used to stain both live and dead cells; propidium iodide is a red-fluorescent nucleic acid stain that is membrane impermeable to viable cells but stains DNA or RNA of dead cells with compromised membranes and emits red (∼617 nm) fluorescence, indicating cell death. Upon the completion of the above treatment, a 1:1 ratio mixture of the two dyes was prepared and added into the samples (2.4 μL mixed dyes for 500 μL suspension) and incubated for 15 min in the dark. Bacteria were then examined under a 40 oil objective on a Zeiss LSM 510 Meta confocal laser scanning microscope and an Accuri C6 flow cytometer (Accuri Cytometers, Inc. Ann Arbor, MI, USA) to identify and quantify those live and dead bacteria. To verify that the microcentrifuge tubes do not affect biocidal activity or EO-OPE-1s, parallel control experiments with quartz cuvettes were carried out. There was found to be no significant difference between the two systems. Timed control experiments for each bacterium were carried out, demonstrating that the 365 nm irradiation does not appear to impact E. coli and S. epidermidis on the time scales of our testing, but there are significant kills for S. aureus after about 1.5 h, which is consistent with literature reports.20

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SUPPORTING INFORMATION AVAILABLE Detailed synthesis of the oligomers and their physical properties; biocidal activity against S. epidermidis, S. aureus, and E. coli; transient absorption spectra as a function of time; absorption spectra of the oligomers; and photophysical data. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION (14)

Corresponding Author: *To whom correspondence should be addressed. E-mail: Whitten@ unm.edu.

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ACKNOWLEDGMENT This research is financially supported by

the Defense Threat Reduction Agency (Contract No. W911NF-071-0079). We thank Mr. Ken Sherrell and the University of New Mexico Mass Spectrometry Facility for assistance with the characterization of the EO-OPE-1s. Confocal images were obtained using a confocal laser scanning microscope housed in the UNM Keck Nanofluidics Laboratory in the Center for Biomedical Engineering.

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âEnd-Onlyâ Functionalized Oligo(phenylene ethynylene)s: Synthesis

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