Microbially Mediated Abiotic Transformation of the Antimicrobial Agent

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Microbially Mediated Abiotic Transformation of the Antimicrobial Agent Sulfamethoxazole under Iron-Reducing Soil Conditions Jessica L. Mohatt, Lanhua Hu, Kevin T. Finneran,† and Timothy J. Strathmann* Department of Civil and Environmental Engineering, University of Illinois at Urbana
Champaign, Urbana, Illinois 61801, United States

bS Supporting Information ABSTRACT: Large quantities of antimicrobial agents used in livestock production are released to soils by land application of manure, but only limited information is available on mechanisms that contribute to antimicrobial fate in soils under variable biogeochemical conditions. Dissipation of the sulfonamide antimicrobial sulfamethoxazole was examined in soil microcosms incubated under different terminal electron-accepting conditions (aerobic, nitrate-reducing, Fe(III)-reducing, and sulfate-reducing). Somewhat unexpectedly, sulfamethoxazole dissipation was fastest under Fe(III)-reducing conditions, with concentrations decreasing by >95% within 1 day. The rapid transformation was attributed to abiotic reactions between sulfamethoxazole and Fe(II) generated by microbial reduction of Fe(III) soil minerals. Separate experiments demonstrated that sulfamethoxazole was abiotically transformed in Fe(II)-amended aqueous suspensions of goethite (R-FeOOH(s)), and observed rate constants varied with the extent of Fe(II) sorption to goethite. Sulfamethoxazole transformation is initiated by a 1-electron reductive cleavage of the N
O bond in the isoxazole ring substituent, and observed products are consistent with Fe(II)-mediated reduction and isomerization processes. These findings reveal potentially important, but previously unrecognized, pathways that may contribute to the fate of sulfamethoxazole and related chemicals in reducing soil environments.

’ INTRODUCTION For several decades, antimicrobial agents have been used to treat and prevent diseases in animals and as feed additives to promote rapid livestock growth.1 Large fractions of the administered doses are excreted unaltered or as metabolites that can be reconverted to the parent compound in the environment.2,3 Livestock manure is often applied to fields as fertilizer, and effluent from wastewater treatment plants is increasingly being used for irrigation, leading to large inputs of antimicrobials and other feed additives (e.g., hormones) to soils, sometimes as high as kg/hectare levels.4 Antimicrobials are also present in landapplied biosolids from wastewater treatment facilities.5 Land application of manure and biosolids can lead to contamination of groundwater and surface waters.6,7 This has raised concerns about the spread of antibiotic resistance resulting from increased selective pressure on exposed microbial communities, potentially leading to proliferation of resistant pathogens.8,9 Even though detected levels of antimicrobials are low (ng/L to μg/L), reports indicate that some antimicrobials may still be capable of altering microbial community structure in impacted environments at these concentrations,10,11 and there remains uncertainty about the effects of exposure to subinhibitory concentrations of antimicrobials on the development of antibiotic resistance in environmental microbial communities.12 Sulfonamide antimicrobials are bacteriostatic agents widely used in human medicine and livestock production.4 Sulfonamides, r 2011 American Chemical Society

including the commonly administered sulfamethoxazole (SMX), are synthetic compounds derived from sulfanilic acid that differ in the N-bound substituent of the sulfonamide linkage (a methyl isoxazole ring in SMX). They are among the most frequently detected pharmaceuticals in occurrence surveys of aquatic and terrestrial environments.2,13,14

To provide an adequate risk assessment of current land application practices, it is imperative that we improve understanding of the processes and environmental factors that govern the fate of sulfonamides and other antimicrobials. Sulfonamides sorb weakly to most soils and exhibit greater mobility than other classes of antimicrobials, like tetracyclines and fluoroquinolones.4 Recent studies have examined the degradation of sulfonamides in soils and sediments, with an emphasis on biodegradation Received: February 4, 2011 Accepted: April 20, 2011 Revised: April 15, 2011 Published: May 04, 2011 4793

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Environmental Science & Technology processes.4,15
17 Factors that have been reported to affect the rates of sulfonamide biodegradation include soil type, moisture content, presence of manure amendments, initial sulfonamide concentration, and prior microbial acclimation.15,16,18 Abiotic degradation pathways may also contribute to sulfonamide fate in soils. Oxidation of aromatic amines by manganese dioxide minerals has been well documented,19 and recent work reported oxidation of the sulfonamides by MnO2(s).20 To date, most studies addressing the fate of sulfonamides in soils have been limited to aerobic conditions. However, soil redox conditions can vary spatially and can change rapidly following episodic flooding of fields, but very little is known about sulfonamide fate in soils under anoxic conditions. Yang and co-workers21 reported that sulfadiazine was much more persistent in soils incubated under anoxic conditions when compared with aerobic conditions, dissipating at rates similar to sterile controls. Wolt and co-workers22 also reported slow transformation (t1/2 = 183 days) of flumetsulam, a sulfonamide herbicide, in anoxic sediment maintained under sulfate-reducing or methanogenic conditions, but direct comparison with aerobic and other terminal electronaccepting process (TEAP) conditions was not reported. Abiotic processes unique to anoxic environments may also contribute to sulfonamide degradation. In particular, many contaminants react with reduced iron and sulfur compounds that are microbially generated in Fe(III)- and sulfate-reducing environments.23
35 To our knowledge, there are no previous reports of such reactions contributing to the degradation of sulfonamides. This contribution reports for the first time on novel microbially mediated abiotic transformation mechanisms for SMX that were suggested by results of soil microcosm experiments conducted under Fe(III)-reducing conditions. Specific objectives of the study were to (i) examine the influence of varying TEAPs on SMX fate in saturated agricultural soil microcosms, (ii) characterize abiotic reactions between SMX and Fe(II), which is microbially generated in soil microcosms under Fe(III)-reducing conditions, (iii) determine the effects of Fe(II) speciation on reaction kinetics, (iv) identify the Fe(II)-reactive functional group in the SMX structure, and (v) identify reaction products and elucidate important SMX transformation pathways initiated by the reaction with Fe(II). Results from this study indicate a new mechanism that may play an important, but previously unrecognized, role in the fate of SMX and related micropollutants in subsurface environments.

’ EXPERIMENTAL SECTION Reagents and Soil. A complete list of reagents is provided in Supporting Information (SI). A poorly crystalline Fe(III) oxyhydroxide soil amendment was prepared as described previously.36 A synthetic goethite (R-FeOOH; Bayferrox 910) obtained from Bayer was used in abiotic batch reactions. The crystal structure has been verified by X-ray diffraction and M€ossbauer spectroscopy, and the N2 BET specific surface area is 15.0 m2/g.37 Agricultural topsoil was collected from a soybean field on the University of Illinois south farms. The soil was homogenized and sieved to remove particles greater than 2.36 mm. Soil analyses (A&L Great Lakes Laboratories, Fort Wayne, IN; see SI for details) revealed a silt clay loam with 48% silt, 36% clay, and 16% sand. The soil contains 4.7% organic matter and 1.1% iron, and the measured soil pH is 6.9. A 5-min Mehlich III extraction yielded 3150 ppm Ca, 410 ppm Mg, 196 ppm K, 37 ppm Fe, 32 ppm Mn, 10 ppm S, 9.9 ppm Zn, and 2.6 ppm Cu.

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Soil Microcosms. A series of batch soil microcosm experiments were first conducted to assess the effects of varying the dominant microbial TEAPs on SMX fate. Microcosms were prepared in triplicate for each TEAP condition after adding 30 g of dry soil to 50 mL of sterilized water in sterilized glass serum bottles. As described in detail in SI, four different TEAPs (aerobic, nitrate-reducing, Fe(III)-reducing, and sulfate-reducing conditions) were first established in separate microcosms using the native soil microbial community. Then, 25 μM SMX was introduced, and its aqueous concentration was monitored for >40 days or until SMX concentrations decreased by >95% (i.e., [SMX] sulfate-reducing > aerobic . nitrate reducing conditions ≈ sterile soil. No significant dissipation of SMX was observed in the sterile water control, verifying that hydrolysis is not significant. Approximately 30% SMX was lost from solution in the sterile soil control, mostly over the first few days, and was attributed to sorption. The soil contains 4.7% organic matter and has significant clay content, both properties that have been shown to promote sulfonamide sorption.4,40 SMX dissipation in nitrate-reducing microcosms was not greatly increased relative to the sterile soil control, suggesting it is not a critical TEAP for SMX transformation. However, it is unclear whether the small increase in SMX loss was due to microbial transformation or instead to changes in SMX sorption resulting from differences in solution ionic composition or changes in soil properties caused by autoclave sterilization. In contrast to nitrate-reducing microcosms, SMX dissipation observed in microcosms incubated under other TEAP conditions was much greater than in the sterile controls. Under aerobic conditions, SMX concentration decreased by >95% within two weeks, similar to previously reported rates of dissipation.17 SMX dissipated more rapidly under Fe(III)-reducing and sulfate-reducing TEAP conditions. In particular, >95% of SMX was lost from solution in 95% in 90% of SMX was degraded within 12 h in suspensions containing both Fe(II) and goethite. The kinetics of SMX degradation observed in Fe(II)/goethite suspensions exhibited a two-stage kinetic behavior, where reaction slowed slightly following the first reaction half-life. The two-stage behavior is apparent when comparing experimental data in Figure 2A with pseudo-first-order kinetics model (eq 1) predictions ½SMXt ¼ e
kobs t ½SMX0

ð1Þ

where [SMX]t and [SMX]0 are the concentrations of SMX at times t and zero, respectively, and kobs (h
1) is the initial pseudofirst-order rate constant determined from least-squares fit of kinetic data collected over the first reaction half-life [3.5((0.1)  10
1 h
1 in Figure 2A; uncertainty = 1σ]. The requirement of both Fe(II) and goethite for SMX degradation is similar to reports of Fe(II) reactions with many other contaminants, including nitro-organics, halogenated alkanes, U(VI), and nitrite,23,24,30,32,43,44 and has been attributed to enhanced reactivity of Fe(II) species that are either adsorbed to or incorporated into the structure of mineral surfaces.23,45 Analogous to aqueous complexation reactions with Fe(III)stabilizing O-donor ligands, Fe(II) adsorption by complexation with surface hydroxyl groups lowers the standard reduction potential of the Fe(III)/Fe(II) redox couple, making Fe(II) a stronger reductant.23,29 Replacement of Fe(II)-coordinated H2O molecules by more electron-donating Lewis base groups has also been suggested to make Fe(II) a better reductant by increasing electron density on the Fe(II) reaction center.23,30 Results presented in Figure 2B
C support the conclusion that the reactive Fe(II) species is associated with the goethite surface. The figures show the effects of goethite loading and pH on both the extent of Fe(II) sorption (symbols, left axis) and kobs for SMX degradation (bars, right axis). Parallel trends were observed for the two variables, increasing with increasing goethite loading and pH, consistent with reactions involving sorbed Fe(II) species. Although the general trends were similar, a direct linear relationship between kobs and the %Fe(II) sorbed was not observed, indicating that additional factors contributed to abiotic SMX transformation (e.g., presence of multiple sorbed Fe(II) species with variable reactivity).28,30 Recent reports indicate that the aqueous uptake of Fe(II) by Fe(III) hydr(oxide) minerals includes contributions from interfacial electron transfer processes in addition to surface

complexation,45 complicating efforts to quantitatively describe Fe(II) speciation at aqueous
mineral interfaces. Separate experiments also showed that SMX was transformed in aqueous solution containing Fe(II) complexes with the catecholate ligand tiron (Figure S2 in SI), which have previously been shown to rapidly reduce nitro-organic and halogenated alkane contaminants.25
27 Thus, the same factors reported to activate Fe(II) for reaction with such contaminants may also promote reactions with SMX and related chemicals. Identification of Fe(II)-Reactive Functional Group. The Fe(II)-reactive functional group within the SMX structure was identified by measuring the reactivity of related sulfonamide antimicrobials and two compounds that are analogues of specific regions in the SMX structure (so-called substructural analogues) in Fe(II)amended goethite suspensions (Figure 3). Of the sulfonamides tested, significant loss from solution was only observed for SMX and sulfisoxazole (SXZ), whereas no dissipation of sulfamerazine (SRZ), sulfamethizole (SMZ), or sulfathiazole (STZ) was observed. Sorption-control experiments (Table S3 in SI) show that, in contrast to SMX and other analogues, SXZ sorbs to goethite at the conditions examined. However, the extent of sorption measured after 3 h (37%) (same amount of time used in batch reactions with Fe(II) þ goethite) was significantly lower than the total loss of SXZ observed in Fe(II)amended goethite suspensions (77%), indicating that reaction with Fe(II) and sorption both contributed to the measured kobs value. Both SMX and SXZ contain five-member isoxazole rings as the N-bound substituent, whereas the other tested sulfonamides possess different heterocyclic rings in their structures. The importance of the isoxazole ring to SMX reactivity with Fe(II) was further supported by the observed reactivity of substructural analogues. Whereas 3-amino-5methylisoxazole (ISX), an analogue of the isoxazole ring structure in SMX, was degraded, no reactivity was observed for sulfanilamide (SAM), an analogue for the aniline and sulfone regions of the parent structure. These findings are also supported by previous reports on reduction of isoxazole compounds, including synthetic applications using FeCl2,46,47 where reaction is initiated by a one-electron reductive cleavage of the isoxazole N
O bond:

Reaction Products. Four reaction products were identified by LC-MS/MS that support the conclusion inferred from the structure
reactivity analysis that Fe(II) is reacting with the isoxazole ring. An LC-MS total ion chromatogram obtained for SMX reaction in Fe(II)-amended suspensions of goethite is provided in SI (Figure S3). Table 1 summarizes LC-MS/MS data and shows proposed structures of the abiotic reaction products. The proposed structures are consistent with masses of the detected pseudomolecular ions and MS/MS fragments (see Table S4 in SI), but unequivocal structural identification would require comparison with reference standards or further spectroscopic information like NMR. Structural changes in the proposed products are summarized as follows. All products exhibit changes to the isoxazole ring and no changes to the aniline ring portion of the structure. In addition, the linking SO2 group is cleaved from one product. Although all the products are believed to result from a common Fe(II) redox-initiated reaction (see next section), only product III is formally reduced by 4796

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Figure 3. Comparison of initial pseudo-first-order rate constants for transformation of SMX and structurally related compounds in Fe(II)-amended aqueous suspensions of goethite. Error bars represent lσ uncertainty determined from triplicate data. Reaction conditions: 50 μM target chemical, 0.5 mM Fe(II), 8 g/L goethite, pH 7.5, I = 0.2.

Table 1. Products of Abiotic SMX Reactions in Fe(II)-Amended Aqueous Goethite Suspensions Detected by LC-MS/MS

a Mass for pseudomolecular ion formed by protonation of the neutral molecule shown in the structure. b Molecular formula of the neutral molecule. c Indicates most abundant fragment ion in MS/MS spectrum. d Structural interpretations of MS/MS fragments provided in Table S4 in SI.

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Scheme 1

2 electrons, whereas the other three products exhibit no net change in oxidation state relative to SMX. Microbially Mediated-Abiotic Transformation Pathway. The rapid transformation of SMX observed under Fe(III)-reducing TEAP conditions is consistent with a microbially mediated-abiotic mechanism:

Dissimilatory Fe(III)-reducing soil microorganisms respire by coupling the oxidation of organic substrates with the reduction of Fe(III) soil minerals to generate Fe(II),36 which in turn can sorb to soil minerals and abiotically initiate the transformation of SMX and other contaminants.48 For SMX, it is proposed that the initial reaction with Fe(II) cleaves the isoxazole N
O bond (eq 2) and forms an unstable radical anion (A; SMX•-) that can then react by several pathways illustrated in Scheme 1 leading to the proposed stable endproduct structures listed in Table 1. In pathway A, the radical anion intermediate accepts a second electron and two protons to produce the reduced β-aminoenone (product III). Reductive

transformation of isoxazoles to β-aminoenones is well documented, including reactions with FeCl2.46,47 In pathway B, A undergoes recyclization to form azirine intermediates, B and C, and returns an electron to Fe(III).46 FeCl2-promoted isomerization of isoxazoles in acetonitrile has been reported to be stabilized by nonalkyl or aryl electrondonating amino and methoxy ring substituents, similar to the bridging nitrogen group that links the isoxazole ring to the sulfanilic acid group.46 Although mass spectrometry data for product II is consistent with C, Zhou and Moore49 reported in photochemical transformation studies that the azirine intermediate quickly rearranges to form an oxazole ring-substituted isomer of SMX (product II) via a nitrile ylide intermediate D. This conversion was also supported by close agreement between the UV spectrum of product II (Figure S4 in SI) and spectral data previously reported for the oxazole ring-substituted isomer.49 Product IV can form by acid-catalyzed hydrolytic cleavage of the strained azirine ring in C. In pathway C, it is proposed that product I forms via an intramolecular free radical aromatic substitution reaction analogous to a Fe(II)-catalyzed Pschorr cyclization.50 Protonation of A and subsequent keto
enol tautomerization yields an imino radical intermediate E that can attack the aromatic ring adjacent to the sulfonamide group. The resulting bicyclic radical intermediate F then exchanges an electron with Fe(III) and loses 4798

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Environmental Science & Technology a proton to form G,50 and subsequent hydrolysis of the sulfonamide group yields product I.51,52 Environmental Significance. This work demonstrates new, but potentially significant, pathways that may contribute to the degradation of sulfamethoxazole in Fe(III)-reducing subsurface environments. The occurrence of these pathways in natural environments can be confirmed using modern analytical approaches (e.g., HR-MS) to screen for expected transformation products (Table 1).53 These pathways are also likely to be important for a number of other isoxazole-containing chemicals, including natural products, herbicides (e.g., isoxaflutole), and other drugs (e.g., valdecoxib). The susceptibility of isoxazolecontaining chemicals to reductive transformation can potentially be exploited to develop pharmaceuticals and agrochemicals that will be less persistent if accidentally released into subsurface environments that are often characterized by reducing conditions. Still, further research is needed to assess the general applicability of the findings to more structurally diverse isoxazole-containing compounds. Like most abiotic reductive transformation processes, Fe(II) reactions with SMX and other isoxazole-containing sulfonamide antimicrobials yield organic transformation products with unknown properties. Most of the identified products retain the core sulfanilamide group, so it is possible that the products have some level of residual antimicrobial activity that would continue to exert selective pressures on soil microbial communities and affect the prevalence of resistant bacteria.8,12 Recent studies have shown that transformation of SMX by reactions with ozone, hydroxyl radical, and UV photolysis generates products exhibiting negligible antimicrobial growth-inhibition potential in comparison to the parent compound.54,55 Similar studies are needed to critically assess the effects of Fe(II)-mediated transformation processes on antimicrobial activity of sulfonamides. In addition, the effects of Fe(II)-mediated SMX transformation on other fate-controlling processes (e.g., sorption, oxidative coupling reactions) are unknown, but potentially important to the overall risks posed by subsurface release of the antimicrobial agent. Although this contribution did not investigate in detail the mechanism(s) responsible for the accelerated SMX dissipation observed under sulfate-reducing conditions, it is presumed that similar microbially mediated abiotic mechanisms are responsible, involving either sorbed Fe(II) or reduced sulfur species (e.g., FeS(s)) as the active reductant.23,33 The agricultural soil used in microcosm experiments contains 1.1% iron, so it is likely that significant Fe(II) was generated through dissimilatory Fe(III) reduction processes before the onset of sulfate reduction, so formation of both sorbed Fe(II) species and precipitated Fe sulfide minerals is highly favorable. Finally, the unexpected reductive transformation of SMX highlights the need for researchers to expand the range of organic compounds for which such pathways are considered in environmental fate analyses. To date, most studies on reductive transformation processes have focused on a narrow range of chemicals for which such pathways are already well established (principally halogenated and nitro-containing organics). It is likely, though, that many more chemicals containing other oxidized moieties like the N
O linkages in isoxazole rings and oxime carbamate pesticides29 are also subject to reductive transformation. Potential reducible functional groups can be identified by examining the rich body of synthetic chemistry literature where reductive transformations are exploited to produce desired intermediates and endproducts.46,47

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’ ASSOCIATED CONTENT

bS

Supporting Information. Listing of chemical reagents, description of procedures and amendments used to establish TEAP conditions, contaminant sorption control experiments, details of soil characterization and analytical methods, figures showing sterilized microcosm data, SMX reduction by Fe(II)tiron complexes, an LC-ESI(þ)-MS total ion chromatogram, structural interpretations of MS/MS fragments, and the UV
vis spectrum of product II are provided. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]; phone: 217-244-4679; fax: 217333-6968. Present Addresses †

Department of Environmental Engineering and Earth Sciences, Clemson University, Clemson, SC 29634.

’ ACKNOWLEDGMENT Financial support was provided by the National Science Foundation Division of Chemical, Bioengineering, Environmental, and Transport Systems (CBET-0746453). J.L.M. was also supported by a Graduate Assistance in Areas of National Need (GAANN) fellowship (P200A060190-08). Na Wei, Kayleigh Dunnett, Sean Carbonaro, and Tias Paul (UIUC) provided assistance with experiments. The manuscript also benefited greatly from feedback provided by four anonymous reviewers. ’ REFERENCES (1) National Research Council. The Use of Drugs in Food Animals: Benefits and Risks; National Academy Press: Washington, DC, 1999. (2) G€obel, A.; Thomsen, A.; McArdell, C. S.; Joss, A.; Giger, W. Occurrence and Sorption Behavior of Sulfonamides, Macrolides, and Trimethoprim in Activated Sludge Treatment. Environ. Sci. Technol. 2005, 39, 3981–3989. (3) Chee-Sanford, J. C.; Mackie, R. I.; Koike, K.; Krapac, I. G.; Lin, Y.-F.; Yannarell, A. C.; Maxwell, S.; Aminov, R. I. Fate and Transport of Antibiotic Residues and Antibiotic Resistance Genes following Land Application of Manure Wastes. J. Environ. Qual. 2009, 38, 1086–1108. (4) Thiele-Bruhn, S. Pharmaceutical Antibiotic Compounds in Soils—A Review. J. Plant Nutr. Soil Sci. 2003, 166 (2), 145–167. (5) Kinney, C. A.; Furlong, E. T.; Zaugg, S. D.; Burkhardt, M. R.; Werner, S. L.; Cahill, J. D.; Jorgensen, G. R. Survey of Organic Wastewater Contaminants in Biosolids Destined for Land Application. Environ. Sci. Technol. 2006, 40, 7207–7215. (6) Pedersen, J. A.; Soliman, M. A.; Suffet, I. H. Human Pharmaceuticals, Hormones, and Personal Care Product Ingredients in Runoff from Agricultural Fields Irrigated with Treated Wastewater. J. Agric. Food Chem. 2005, 53, 1625–1632. (7) Topp, E.; Monteiro, S. C.; Beck, A.; Coelho, B. B.; Boxall, A. B. A.; Duenk, P. W.; Kleywegt, S.; Lapen, D. R.; Payne, M.; Sabourin, L.; Li, H.; Metcalfe, C. D. Runoff of Pharmaceuticals and Personal Care Products following Application of Biosolids to an Agricultural Field. Sci. Total Environ. 2008, 396, 52–59. (8) Anderson, A. D.; Nelson, J. M.; Rossiter, S.; Angulo, F. J. Public Health Consequences of Use of Antimicrobial Agents in Food Animals in the United States. Microb. Drug Resist. 2003, 9, 373–379. (9) Baquero, F.; Martinez, J.-L.; Canton, R. Antibiotics and Antibiotic Resistance in Water Environments. Curr. Opin. Biotechnol. 2008, 19, 260–265. 4799

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