Sulfonamide Class Research Articles

A generic approach for expanding homolog-targeted residue screening of sulfonamides using a fast matrix separation and class-specific fragmentation-dependent acquisition with a hybrid quadrupole-linear ion trap mass spectrometer

A generic and efficient homolog-targeted approach was used to expand screening and detection of target class of sulfonamides and structural analogs, based on a fast single-tube extraction/partitioning-multifunction adsorption cleanup (SEP/MAC) for class-specific fragmentation-dependent acquisition with a liquid chromatography–hybrid triple-quadrupole linear ion trap mass spectrometer (LC–QqLIT). By combining the two-stage process conducted in a single tube as one-pot protocol, the straightforward SEP/MAC procedure was optimized to offer clean extracts with reasonable recovery (71–109% with RSDs<20%) and decreased matrix interferences (−9 to 19%) of multiresidual sulfonamide extraction from different tissue samples. The novel use of neutral loss scan of 66Da (NLS) or precursor ion scanning of m/z 108 (PreS) in positive ion mode was found to achieve more comprehensive coverage of protonated molecular ions of a wide array of sulfonamides including N4-acetyl and hydroxylamine metabolites plus their possible dimers. Moreover, the PreS-triggered automatically enhanced product ion spectral acquisition enabled simultaneous screening, profiling and confirmation of an unlimited number of analytes belonging to the sulfonamide class within a single analysis. The validation and application results of the generic SEP/MAC-based LC–QqLIT strategy consistently demonstrated favorable performances with acceptable accuracy (67–116%), precision (RSDs<25%), and sensitivity (LOQs≤7.5ngg−1) to meet the acceptance criteria for all the sulfonamide–tissue combinations. Thus, the integration of the matrix-independent SEP/MAC procedure and the multiparameter matching algorithm with the unit-resolution LC–QqLIT instrument can serve as a valuable semi-targeted discovery strategy for rapid screening and reliable quantitative/confirmatory analysis of real samples.

Occurrence and assessment of veterinary antibiotics in swine manures: A case study in East China

We investigated the occurrence of 14 selected antibiotics including five therapeutic classes of tetracyclines, sulfonamides, macrolides, fluoroquinolones and chloramphenicols in manures collected from four swine farms of different sizes in eastern China. Tetracyclines (tetracycline, oxytetracycline, chlortetracycline, and doxycycline) and sulfadiazine were the most prominent contaminants in the manure samples, with maximum concentrations reaching 98.2 x 10(3), 354.0 x 10(3), 139.4 x 10(3), 37.2x 10(3), and 7.1x 10(3) mu g/kg, respectively. The occurrence of these compounds was dependent on breeding scale, animal type, and breeding season. Manure storage and vermiculture were not able to effectively deplete the heavier contaminants (tetracyclines and sulfadiazine), resulting in high levels of these chemicals remaining in manures. Therefore, the occurrence of these antibiotics in agricultural soils (0.1-205.1 mu g/kg) collected from four types of agricultural land (pear orchard, tea plantation, bamboo forest, and paddy field) near the studied farms, was a reflection of manure application. However, the extremely high concentrations of antibiotics in manures were unlikely from feed consumption, but from other direct forms of medicine application.

Evidence for a Complex Relationship between Antibiotics and Antibiotic-Resistant Escherichia Coli: From Medical Center Patients to a Receiving Environment

The aim of this study was to investigate the relationship between antibiotics and antibiotic-resistant fecal bacteria (E. coli) in water along a medical center-wastewater treatment plant-river continuum (4 km). A multiresidue chemical analysis methodology, using solid phase extraction coupled with liquid chromatography tandem mass spectrometry, was performed to detect whether low levels of contamination by 34 antibiotics were related to antibiotic resistance of E. coli and antibiotic use. The contamination of water by antibiotics and antibiotic-resistant E. coli decreased along the continuum. Although amoxicillin was predominantly prescribed, only ofloxacin (1 ng·L(-1)) and sulfamethoxazole (4 ng·L(-1)) persisted in the river. At the retirement home, in the medical center, even though no tetracycline and sulfamethoxazole were consumed, the highest occurrences of antibiotic resistance were in classes of quinolones (42.0%), sulfonamides (24.0%), tetracyclines (38.0%), and penicillins (38.0%), mainly due to the presence of multiple antibiotic-resistance genes on class 1 integrons. Along the continuum, the occurrence of E. coli resistant to antibiotics and those carrying class 1 integrons decreased in water samples (p-value <0.001). Interestingly, in the river, only persistent antibiotic compounds (ofloxacin, sulfamethoxazole) were found, but they did not correspond to the major resistances (tetracycline, amoxicillin) of E. coli.

Excretion of Antibiotic Resistance Genes by Dairy Calves Fed Milk Replacers with Varying Doses of Antibiotics

Elevated levels of antibiotic resistance genes (ARGs) in soil and water have been linked to livestock farms and in some cases feed antibiotics may select for antibiotic resistant gut microbiota. The purpose of this study was to examine the establishment of ARGs in the feces of calves receiving milk replacer containing no antibiotics versus subtherapeutic or therapeutic doses of tetracycline and neomycin. The effect of antibiotics on calf health was also of interest. Twenty-eight male and female dairy calves were assigned to one of the three antibiotic treatment groups at birth and fecal samples were collected at weeks 6, 7 (prior to weaning), and 12 (5 weeks after weaning). ARGs corresponding to the tetracycline (tetC, tetG, tetO, tetW, and tetX), macrolide (ermB, ermF), and sulfonamide (sul1, sul2) classes of antibiotics along with the class I integron gene, intI1, were monitored by quantitative polymerase chain reaction as potential indicators of direct selection, co-selection, or horizontal gene transfer of ARGs. Surprisingly, there was no significant effect of antibiotic treatment on the absolute abundance (gene copies per gram wet manure) of any of the ARGs except ermF, which was lower in the antibiotic-treated calf manure, presumably because a significant portion of host bacterial cells carrying ermF were not resistant to tetracycline or neomycin. However, relative abundance (gene copies normalized to 16S rRNA genes) of tetO was higher in calves fed the highest dose of antibiotic than in the other treatments. All genes, except tetC and intI1, were detectable in feces from 6 weeks onward, and tetW and tetG significantly increased (P < 0.10), even in control calves. Overall, the results provide new insight into the colonization of calf gut flora with ARGs in the early weeks. Although feed antibiotics exerted little effect on the ARGs monitored in this study, the fact that they also provided no health benefit suggests that the greater than conventional nutritional intake applied in this study overrides previously reported health benefits of antibiotics. The results suggest potential benefit of broader management strategies, and that cost and risk may be avoided by minimizing incorporation of antibiotics in milk replacer.

MULTICLASS RESIDUES SCREENING OF 105 VETERINARY DRUGS IN MEAT, MILK, AND EGG USING ULTRA HIGH PERFORMANCE LIQUID CHROMATOGRAPHY TANDEM QUADRUPOLE TIME-OF-FLIGHT MASS SPECTROMETRY

A high-throughput and robust method for analyzing multiclass residues of veterinary drugs in meat, milk, and egg by ultra-high performance liquid chromatography (UHPLC)–quadrupole time-of-flight mass spectrometry (QTOF) was established. The method successfully applied to the screening, quantification, and confirmation of 105 compounds from 9 different classes of drugs, including beta-agonists, benzimidazoles, corticoides, triphenylmethane, nitromidazoles, quinolones, sulfonamides, tetracylines, and benzodiazepams. The samples are extracted by a single extraction using acetonitrile containing 0.1% formic acid, followed by an easy solid phase extraction (SPE) clean-up on HLB column and finally analyzed by LC/MS QTOF MS. The separation was achieved within 30 min at the optimized chromatographic conditions. More than 92% compounds in this study can be reliably identified based on accurate mass measurement (within the 3 ppm mass error) at the 5 µg/kg concentration levels in the complex food matrix with further MS/MS confirmation. Our study demonstrated a reliable, high-efficient and high-sensitive strategy for the fast and high throughput screening of multiclass of veterinary drugs in foodstuffs of animal origin.

Development of a Pterin-Based Fluorescent Probe for Screening Dihydropteroate Synthase

Dihydropteroate synthase (DHPS) is the classical target of the sulfonamide class of antimicrobial agents, whose use has been limited by widespread resistance and pharmacological side effects. We have initiated a structure-based drug design approach for the development of novel DHPS inhibitors that bind to the highly conserved and structured pterin subsite rather than to the adjacent p-aminobenzoic acid binding pocket that is targeted by the sulfonamide class of antibiotics. To facilitate these studies, a robust pterin site-specific fluorescence polarization (FP) assay has been developed and is discussed herein. These studies include the design, synthesis, and characterization of two fluorescent probes, and the development and validation of a rapid DHPS FP assay. This assay has excellent DMSO tolerance and is highly reproducible as evidenced by a high Z' factor. This assay offers significant advantages over traditional radiometric or phosphate release assays against this target, and is suitable for site-specific high-throughput and fragment-based screening studies.

Effect of Various Sludge Digestion Conditions on Sulfonamide, Macrolide, and Tetracycline Resistance Genes and Class I Integrons

Wastewater treatment processes are of growing interest as a potential means to limit the dissemination of antibiotic resistance. This study examines the response of nine representative antibiotic resistance genes (ARGs) encoding resistance to sulfonamide (sulI, sulII), erythromycin (erm(B), erm(F)), and tetracycline (tet(O), tet(W), tet(C), tet(G), tet(X)) to various laboratory-scale sludge digestion processes. The class I integron gene (intI1) was also monitored as an indicator of horizontal gene transfer potential and multiple antibiotic resistance. Mesophilic anaerobic digestion at both 10 and 20 day solids retention times (SRTs) significantly reduced sulI, suII, tet(C), tet(G), and tet(X) with longer SRT exhibiting a greater extent of removal; however, tet(W), erm(B) and erm(F) genes increased relative to the feed. Thermophilic anaerobic digesters operating at 47 °C, 52 °C, and 59 °C performed similarly to each other and provided more effective reduction of erm(B), erm(F), tet(O), and tet(W) compared to mesophilic digestion. However, thermophilic digestion resulted in similar or poorer removal of all other ARGs and intI1. Thermal hydrolysis pretreatment drastically reduced all ARGs, but they generally rebounded during subsequent anaerobic and aerobic digestion treatments. To gain insight into potential mechanisms driving ARG behavior in the digesters, the dominant bacterial communities were compared by denaturing gradient gel electrophoresis. The overall results suggest that bacterial community composition of the sludge digestion process, as controlled by the physical operating characteristics, drives the distribution of ARGs present in the produced biosolids, more so than the influent ARG composition.

Committee Opinion No. 494: Sulfonamides, Nitrofurantoin, and Risk of Birth Defects

The evidence regarding an association between the nitrofuran and sulfonamide classes of antibiotics and birth defects is mixed. As with all patients, antibiotics should be prescribed for pregnant women only for appropriate indications and for the shortest effective duration. During the second and third trimesters, sulfonamides and nitrofurantoins may continue to be used as first-line agents for the treatment and prevention of urinary tract infections and other infections caused by susceptible organisms. Prescribing sulfonamides or nitrofurantoin in the first trimester is still considered appropriate when no other suitable alternative antibiotics are available. Pregnant women should not be denied appropriate treatment for infections because untreated infections can commonly lead to serious maternal and fetal complications.

Silver Nanocomposite Electrode Modified with Hexacyanoferrate. Preparation, Characterization and Electrochemical Behaviour Towards Substituted Anilines

AbstractA novel conducting silver nanocomposite (nanoAg‐GEC) material for electrochemical sensing of substituted anilines based on silver nanoparticles is presented. For the first time, the in situ growth of silver hexacyanoferrate nanoparticles (nanoAgHCF) on the surface of the silver nanocomposite electrodes was achieved. The surface morphology of the nanoAg‐GEC electrode modified with hexacyanoferrate (nanoAgHCF‐GEC) was investigated using scanning electron microscopy (SEM) coupled with energy‐dispersive X‐ray spectroscopy (EDX). The electrochemical behaviour of the nanoAgHCF‐GEC electrode towards oxidation and reduction of substituted anilines (procaine and sulfamerazine) was investigated by cyclic voltammetry. The results showed a linear dependence in the concentration range studied for each class of sulfonamides.

Acute Parotitis Induced by Trimethoprim/Sulfamethoxazole

Adverse drug reactions to the sulfonamide antibiotics are uncommon. When they do occur, they usually manifest as a rash or urticaria. Our review of the recent literature found that while sialadenitis is listed as a possible side effect of sulfonamide use, no actual case has ever been reported until now. We describe a case of acute bilateral parotitis that arose as a side effect of sulfonamide antibiotic treatment. We also examine the relevance of such pathology to the proposed mechanisms of sialadenitis, and we briefly discuss sulfonamide-induced pancreatitis. Lastly, we review the controversy over the possibility that some adverse drug reactions may be caused by cross-reactivity among different classes of sulfonamides.

Synthesis of bi-substrate state mimics of dihydropteroate synthase as potential inhibitors and molecular probes

The increasing emergence of resistant bacteria drives us to design and develop new antimicrobial agents. Pursuant to that goal, a new targeting approach of the dihydropteroate synthase enzyme, which serves as the site of action for the sulfonamide class of antimicrobial agents, is being explored. Using structural information, a new class of transition state mimics has been designed and synthesized that have the capacity to bind to the pterin, phosphate and para-amino binding sites. The design, synthesis and evaluation of these compounds as inhibitors of Bacillusanthracis dihydropteroate synthase is described herein. Outcomes from this work have identified the first trivalent inhibitors of dihydropteroate synthase whose activity displayed slow binding inhibition. The most active compounds in this series contained an oxidized pterin ring. The binding of these inhibitors was modeled into the dihydropteroate synthase active site and demonstrated a good correlation with the observed bioassay data, as well as provided important insight for the future design of higher affinity transition state mimics.

In vitro antitumor activity of N-glycosyl sulfonamides

A series of α-d-hex-2-enopyranosyl sulfonamides was evaluated for their antiproliferative activity against human hepatocellular liver carcinoma (HepG2) and human lung adenocarcinoma (A549) cell lines. The most potent compound (2,4,6-tri-O-acetyl-3-deoxy-α-d-erythro-hex-2-enopyranosyl ethanesulfonamide) showed antiproliferative properties in the micromolar range. The SARs of these sulfonamidoglycoside which includes the influence of carbohydrate rings and sulfonamide class are described.

Development of a multi-class method for the quantification of veterinary drug residues in feedingstuffs by liquid chromatography-tandem mass spectrometry

A simple multi-residue method was developed for detecting and quantifying 33 analytes from 13 classes of antibiotics (tetracyclines (3), quinolones (7), penicillins (3), ionophore coccidiostats (7), macrolides (3), sulfonamides (1), quinoxalines (2), phenicols (2), lincosamides (1), diaminopyrimidines (1), polypeptides (1), streptogramins (1) and pleuromutilins (1)) in animal feeds. Extraction and clean-up procedures were optimized with spiked piglet feed. Samples were extracted by ultrasonic-assisted extraction with a mixture of methanol/acetonitrile/McIlvaine buffer at pH 4.6 (37.5/37.5/25, v/v/v) containing 0.3% of EDTA-Na 2, followed by a clean up using a dispersive solid-phase extraction (d-SPE) with PSA (primary secondary amine). Detection of antibiotics was achieved by liquid chromatography-electrospray tandem mass spectrometry (LC–ESI-MS/MS) within 28 min using both positive and negative ESI mode. Average recoveries ranged from 51% (oxytetracycline) to 116% (tilmicosin) with associated relative standard deviations of 7.3% and 9.0% and an overall mean of 87%. Limits of quantification ranged from 3.8 ng g −1 (lincomycin) to 65.0 ng g −1 (bacitracin). Following optimization, the method was further verified for bovine and lamb feedingstuffs; negative matrix effects were evaluated and overcome by a standard addition method.

Structural Studies of Pterin-Based Inhibitors of Dihydropteroate Synthase

Dihydropteroate synthase (DHPS) is a key enzyme in bacterial folate synthesis and the target of the sulfonamide class of antibacterials. Resistance and toxicities associated with sulfonamides have led to a decrease in their clinical use. Compounds that bind to the pterin binding site of DHPS, as opposed to the p-amino benzoic acid (pABA) binding site targeted by the sulfonamide agents, are anticipated to bypass sulfonamide resistance. To identify such inhibitors and map the pterin binding pocket, we have performed virtual screening, synthetic, and structural studies using Bacillus anthracis DHPS. Several compounds with inhibitory activity have been identified, and crystal structures have been determined that show how the compounds engage the pterin site. The structural studies identify the key binding elements and have been used to generate a structure-activity based pharmacophore map that will facilitate the development of the next generation of DHPS inhibitors which specifically target the pterin site.

A new class of perfluorinated acid contaminants: Primary and secondary substituted perfluoroalkyl sulfonamides are acidic at environmentally and toxicologically relevant pH values

The SPARC software program was validated for nitrogen-hydrogen acidity constant estimation of primary and secondary sulfonamides against a broad suite of substituted derivatives with experimental datasets in water and dimethylsulfoxide solvent systems and across a wide pKa range. Following validation, amidic proton pKa values were estimated for all C1 through C8 congeners of five major perfluoroalkyl sulfonamide classes: unsubstituted sulfonamides, N-methyl and N-ethyl sulfonamides, sulfonamidoethanols, and sulfonamidoacetates. Branching of the perfluoroalkyl chain is expected to have substantial impacts on amide moiety acidity in these contaminant groups, with intrahomologue variability of up to four pKa units and increasing pKa values with both increasing chain branching and greater proximity of the chain branching to the sulfonamide head group. Perfluoroalkyl chain length is not predicted to have a substantial influence on sulfonamide acidity. The predicted pKa values and variability are anticipated to have substantial impacts on the environmental partitioning and degradation of these compounds, as well as the modes and magnitudes of toxicological effects. Substantial pH dependent isomeric fractionation of perfluoroalkyl sulfonamides is expected both in situ and in vivo, necessitating the incorporation of amide group acidities in multimedia environmental models and pharmacokinetic studies.

A conceptual model describing the fate of sulfadiazine and its metabolites observed in manure-amended soils

Sulfadiazine (SDZ) belongs to the chemical class of sulfonamides, one of the most important groups of antibiotics applied in animal husbandry in Europe. These antibiotics end up in the soil after manure from treated animals is applied as fertilizer. They can inhibit soil microbial functions and enhance the spread of resistance genes among soil microorganisms. In order to assess the exposure of soil microorganisms to SDZ, a conceptual kinetic model for the prediction of temporally resolved antibiotic concentrations in soil was developed. The model includes transformation reactions, reversible sequestration and the formation of non-extractable residues (NER) from SDZ and its main metabolites N 4-acetyl-sulfadiazine (N-ac-SDZ) and 4-hydroxy-sulfadiazine (OH-SDZ). The optimum model structure and rate constants of SDZ kinetics and its metabolites were determined by fitting different model alternatives to sequential extraction data of a manure-amended Cambisol soil. N-ac-SDZ is degraded to SDZ with a half-life of 4 d, whereas OH-SDZ is not. Though, based on the available data, the hydroxylation of SDZ seems to be negligible, it is still included in the model structure since this process has been observed in recent studies. Sequestration into a residual fraction has similar kinetics for SDZ, N-ac-SDZ and OH-SDZ and is one order of magnitude faster than the reverse translocation. The irreversible formation of NER is restricted to SDZ and OH-SDZ. The model shows good agreement when applied to extraction data measured independently for a Luvisol soil. The combination of sequential extraction data and the conceptual kinetic model enables us to gain further insight into the long-term fate and exposure of sulfonamides in soil.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

We report a case of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) secondary to trimethoprim-sulfamethoxazole (TMP-Sx) therapy for presumed community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection. Although the association between SJS/TEN and the sulfonamide class of antibiotics is well established, the increasing prevalence of CA-MRSA has left practitioners with limited regimens to effectively treat skin and soft tissue infections (SSTIs) in the outpatient setting. In the case of SSTIs, alternative treatment of these infections should be considered, especially when the bacterial pathogen is unknown. Future investigations evaluating the efficacy of adjunctive antibiotics for purulent SSTIs and monitoring the incidence of SJS/TEN in the era of CA-MRSA are necessary to reduce unnecessary use of sulfonamide drugs. The potential development of SJS/TEN, a severe life-threatening illness, emphasizes the need for judicious use of TMP-Sx and close monitoring and follow-up for patients who were given TMP-Sx for SSTIs.

4-(4-Bromobenzenesulfonamido)benzoic acid

The title compound, C13H10BrNO4S, belongs to the sulfonamide class of organic compounds. The two aromatic rings are inclined at 34.30 (15)° to one another, and the carboxyl substituent lies in the plane of the benzene ring to which it is bound (maximum deviation = 0.004 Å). In the crystal structure, charactersitic carboxylic acid dimers are formed through O—H⋯O hydrogen bonds. These dimers are linked into rows down a by N—H⋯O inter­actions. Additional C—H⋯O contacts further stabilize the structure, and a close Br⋯Br(x, −y + 1, −z + 1) contact of 3.5199 (9) Å is also observed.

Severe Allergic Reaction to Hydrochlorothiazide Mimicking Septic Shock

Hydrochlorothiazide (HCTZ) is a sulfonamide-containing drug with commonly reported adverse effects that include electrolyte abnormalities, orthostatic hypotension, hyperglycemia, and photosensitivity. A few reports have described rare but serious drug complications such as interstitial pneumonitis, angioedema, and aplastic anemia. We describe a patient who experienced a serious HCTZ-induced adverse event that, to our knowledge, has not yet been reported in the literature. A 78-year-old woman came to the emergency department with dyspnea and severe fatigue; her signs and symptoms were suggestive of septic shock from pneumonia. She was treated accordingly, her condition improved, and she was discharged home. During the next 2 months, the patient returned to the emergency department 2 more times and was hospitalized each time with the same diagnosis. During her third admission, it was discovered that the patient's primary care physician had restarted her HCTZ for hypertension after it had been discontinued during each of the first two hospitalizations. The patient's symptoms began within hours of the first and second hospitalizations and almost immediately after taking a dose of HCTZ on the day of the third hospitalization. Her medical history revealed documented allergic reactions to sulfonamide drugs and penicillin; thus a hypersensitivity reaction to HCTZ was suspected. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship between the patient's hypersensitivity reactions and HCTZ therapy. Because of a lack of evidence showing cross-reactivity among the different classes of sulfonamides, the mechanism of the allergic reaction to HCTZ was unlikely to be cross-sensitivity between sulfonamide antibiotics and sulfonamide nonantibiotic drugs. Although the mechanism is not clear, evidence shows that the allergy to the HCTZ (sulfonamide nonantibiotic) may be due to a predisposition to drug allergies rather than sulfonamide cross-sensitivity. Clinicians should be aware of the potential for these types of allergic reactions.

Targeting the Fatty Acid Biosynthesis Enzyme, β-Ketoacyl−Acyl Carrier Protein Synthase III (PfKASIII), in the Identification of Novel Antimalarial Agents

The importance of fatty acids to the human malaria parasite, Plasmodium falciparum, and differences due to a type I fatty acid synthesis (FAS) pathway in the parasite, make it an attractive drug target. In the present study, we developed and a utilized a pharmacophore to select compounds for testing against PfKASIII, the initiating enzyme of FAS. This effort identified several PfKASIII inhibitors that grouped into various chemical classes of sulfides, sulfonamides, and sulfonyls. Approximately 60% of the submicromolar inhibitors of PfKASIII inhibited in vitro growth of the malaria parasite. These compounds inhibited both drug sensitive and resistant parasites and testing against a mammalian cell line revealed an encouraging in vitro therapeutic index for the most active compounds. Docking studies into the active site of PfKASIII suggest a potential binding mode that exploits amino acid residues at the mouth of the substrate tunnel.