Screening Novel Per- and Polyfluoroalkyl Substances in Human Blood Based on Nontarget Analysis and Underestimated Potential Health Risks.

Nontarget analysis has gained prominence in screening novel perfluoroalkyl and polyfluoroalkyl substances (PFASs) in the environment, yet remaining limited in human biological matrices. In this study, 155 whole blood samples were collected from the general population in Shijiazhuang City, China. By nontarget analysis, 31 legacy and novel PFASs were assigned with the confidence level of 3 or above. For the first time, 11 PFASs were identified in human blood, including C1 and C3 perfluoroalkyl sulfonic acids (PFSAs), C4 ether PFSA, C8 ether perfluoroalkyl carboxylic acid (ether PFCA), C4-5 unsaturated perfluoroalkyl alcohols, C9-10 carboxylic acid-perfluoroalkyl sulfonamides (CA-PFSMs), and C1 perfluoroalkyl sulfonamide. It is surprising that the targeted PFASs were the highest in the suburban population which was impacted by industrial emission, while the novel PFASs identified by nontarget analysis, such as C1 PFSA and C9-11 CA-PFSMs, were the highest in the rural population who often drank contaminated groundwater. Combining the toxicity prediction results of the bioaccumulation potential, lethality to rats, and binding affinity to target proteins, C3 PFSA, C4 and C7 ether PFSAs, and C9-11 CA-PFSMs exhibit great health risks. These findings emphasize the necessity of broadening nontarget analysis in assessing the PFAS exposure risks, particularly in rural populations.

Discovery of non-sulfonamide carbonic anhydrase IX inhibitors through structure-based virtual screening.

Carbonic anhydrase IX (CA IX) is a subtype of the human carbonic anhydrase (hCA) family and exhibits high expression in various solid tumors, rendering it a promising target for tumor therapy. Currently, marketed carbonic anhydrase inhibitors (CAIs) are primarily composed of sulfonamides derivatives, which may have impeded their potential for further expansion. Therefore, we have developed a structure-based virtual screening approach to explore novel CAIs exhibiting distinctive structures and anti-tumor potential in the FDA database. In vitro experiments demonstrated that 3-pyridinemethanol (0.42 µM), procodazole (8.35 µM) and pamidronic acid (8.51 µM) exhibited inhibitory effects on CA IX activity. The binding stability and interaction mode between the CA IX and the hit compounds are further investigated through molecular dynamics simulations and binding free energy calculations. Furthermore, the ADME/Tox prediction results indicated that these compounds exhibited favorable pharmacological properties and minimal toxic side effects. Our study successfully applied computational strategies to discover three non-sulfonamide inhibitors of carbonic anhydrase IX (CA IX) that demonstrate inhibitory activity in vitro. These findings have significant implications for the development of CA IX inhibitors and anti-tumor drugs, contributing to their progress in the field.

Synthesis, molecular docking analysis, drug-likeness evaluation, and inhibition potency of new pyrazole-3,4-dicarboxamides incorporating sulfonamide moiety as carbonic anhydrase inhibitors.

A series of novel pyrazole-dicarboxamides were synthesized from pyrazole-3,4-dicarboxylic acid chloride and various primary and secondary sulfonamides. The structures of the new compounds were confirmed by FT-IR, 1H-NMR, 13C-NMR, and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.024-0.496 µM for hCA I and 0.006-5.441 µM for hCA II. Compounds 7a and 7i showed nanomolar level of inhibition of hCA II, and these compounds exhibited high selectivity for this isoenzyme. Molecular docking studies were performed between the most active compounds 7a, 7b, 7i, and the reference inhibitor AAZ and the hCAI and hCAII to investigate the binding mechanisms between the compounds and the isozymes. These compounds showed better interactions than the AAZ. ADMET and drug-likeness analyses for the compounds have shown that the compounds can be used pharmacologically in living organisms.

Discovery of novel biphenyl-sulfonamide analogues as NLRP3 inflammasome inhibitors.

The aberrant activation of NLRP3 inflammasome has been observed in various human diseases. Targeting the NLRP3 protein with small molecule inhibitors shows immense potential as an effective strategy for disease intervention. Herein, a series of novel biphenyl-sulfonamide NLRP3 inflammasome inhibitors were designed and synthesized. The representative compound H28 was identified as potent and specific NLRP3 inflammasome inhibitor with IC50 values of 0.57 µM. Preliminary mechanistic studies have revealed that compound H28 exhibits direct binding to the NLRP3 protein (KD: 1.15 µM), effectively inhibiting the assembly and activation of the NLRP3 inflammasome. The results in a mouse acute peritonitis model revealed that H28 effectively inhibit the NLRP3 inflammasome pathway, demonstrating their anti-inflammatory properties. Our findings strongly support the further development of H28 as potential lead compound for treating NLRP3-related diseases.

Electrochemical detection of sulfanilamide using tannic acid exfoliated MoS2 nanosheets combined with reduced graphene oxide/graphite.

Sulfonamides are a family of synthetic drugs with a broad-spectrum of antimicrobial activity. Like other antimicrobials, they have been found in aquatic environments, making their detection important. Herein, an electrochemical sensor was designed using tannic acid exfoliated few-layered MoS2 sheets, which were combined with a mixture of reduced graphene oxide (rGO) and graphite flakes (G). The rGO/G was formed using electrodeposition, by cycling from -0.5 to -1.5 V in an acidified sulfate solution with well dispersed GO and G. The exfoliated MoS2 sheets were drop cast over the wrinkled rGO/G surface to form the final sensor, GCE/rGO/G/ta-MoS2. The mixture of rGO/G was superior to pure rGO in formulating the sensor. The fabricated sensor exhibited an extended linear range from 0.1 to 566 µM, with a LOD of 86 nM, with good selectivity in the presence of various salts found in water and structurally related drugs from the sulfonamide family. The sensor showed very good reproducibility with the RSD at 0.48 %, repeatability and acceptable long term stability over a 10-day period. Good recovery from both tap and river water was achieved, with recovery ranging from 90.4 to 98.9 % for tap water and from 83.5 to 94.4 % for real river water samples.

Sulfonamide derivatives with benzothiazole scaffold: Synthesis and carbonic anhydrase I-II inhibition properties.

The secondary sulfonamide derivatives containing benzothiazole scaffold (1-10) were synthesized to determine their inhibition properties on two physiologically essential human carbonic anhydrases isoforms (hCAs, EC, 4.2.1.1), hCA I, and hCA II. The inhibitory effects of the compounds on hCA I and hCA II isoenzymes were investigated by comparing their IC50 and Ki values. The Ki values of compounds (1-10) against hCA I and hCA II are in the range of 0.052 ± 0.022-0.971 ± 0.280 and 0.025 ± 0.010-0.682 ± 0.335, respectively. Some of these inhibited the enzyme more effectively than the standard drug, acetazolamide. In particular, compounds 5 and 4 were found to be most effective on hCA I and hCA II.

Synthesis and evaluation of hybrid sulfonamide-chalcones with potential antileishmanial activity.

Leishmaniasis is an emerging tropical infectious disease caused by a protozoan parasite of the genus Leishmania. In this work, the molecular hybridization between a trimethoxy chalcone and a sulfonamide group was used to generate a series of sulfonamide-chalcones. A series of eight sulfonamide-chalcone hybrids were made with good yields (up to 95%). These sulfonamide-chalcones were tested against promastigotes of Leishmania amazonensis and cytotoxicity against mouse macrophages, which showed good antileishmanial activity with IC50 = 1.72-3.19 µM. Three of them (10c, 10g, and 10h) were also highly active against intracellular amastigotes and had a good selectivity index (SI > 9). Thus, those three compounds were docked in the cytosolic tryparedoxin peroxidase (cTXNPx) enzyme of the parasite, and molecular dynamics simulations were carried out. This enzyme was selected as a target protein for the sulfonamide-chalcones due to the fact of the anterior report, which identified a strong and stable interaction between the chalcone NAT22 (6) and the cTXNPx. In addition, a prediction of the drug-likeness, and the pharmacokinetic profile of all compounds were made, demonstrating a good profile of those chalcones.

The fate of sulfonamides in microenvironments of rape and hot pepper rhizosphere soil system.

Sulfonamides (SAs) in agricultural soils can be degraded in rhizosphere, but can also be taken up by vegetables, which thereby poses human health and ecological risks. A glasshouse experiment was conducted using multi-interlayer rhizoboxes to investigate the fate of three SAs in rape and hot pepper rhizosphere soil systems to examine the relationship between the accumulation and their physicochemical processes. SAs mainly entered pepper shoots in which the accumulation ranged from 0.40 to 30.64 mg kg-1, while SAs were found at high levels in rape roots ranged from 3.01 to 16.62 mg kg-1. The BCFpepper shoot exhibited a strong positive linear relationship with log Dow, while such relationship was not observed between other bioconcentration factors (BCFs) and log Dow. Other than lipophilicity, the dissociation of SAs may also influence the uptake and translocation process. Larger TF and positive correlation with log Dow indicate preferential translocation of pepper SAs. There was a significant (p < 0.05) dissipation gradient of SAs observed away from the vegetable roots. In addition, pepper could uptake more SAs under solo exposure, while rape accumulated more SAs under combined exposure. When SAs applied in mixture, competition between SAs might occur to influence the translocation and dissipation patterns of SAs.

The phloem and xylem structure of plants and the neutral and ionic partitioning of sulfonamides (SAs) influence the uptake and translocation of SAs.A significant (p < 0.05) dissipation gradient of SAs was observed away from the vegetable roots.Combined exposure could promote the correlation between log BCF and log D_ow.

Novel sulfonamide-phosphonate conjugates as carbonic anhydrase isozymes inhibitors.

The three-components one-pot Kabachnik-Fields reaction of sulfapyridine, diethyl phosphite, and aldehyde under thermal catalysis reaction condition in the presence of bismuth (III) triflate as a catalyst afford the corresponding sulfonamide-phosphonates (3a-3p) in good to excellent yields (78%-91%). The structures of the new synthesized compounds were elucidated and confirmed by variable spectroscopic studies. Single crystal X-ray studies for 3a, 3d, and 3i verified the proposed structure. The newly developed sulfonamide-phosphonates were evaluated for their inhibitory properties against four isoforms of human carbonic anhydrase (hCA I, II, IX, and XII). The results demonstrated that they exhibited greater potency in inhibiting hCA XII compared to hCA I, II, and IX, with Ki ranging from 5.1 to 51.1 nM. Compounds 3l and 3p displayed the highest potency, exhibiting selectivity ratios of I/XII >298.7 and 8.5, and II/XII ratios of 678.1 and 142.1, respectively. Molecular docking studies were conducted to explore their binding patterns within the binding pocket of CA XII. The results revealed that the sulfonamide NH group coordinated with the Zn2+ ion, and hydrogen bond interactions were observed with residue Thr200. Additionally, hydrophobic interactions were identified between the benzenesulfonamide phenyl ring and Leu198. Compounds 3p and 3l exhibited an additional hydrogen bonding interaction with other amino acid residues. These supplementary interactions may contribute to the enhanced potency and selectivity of these compounds toward the CA XII isoform.

2-Thioxo-3,4-dihydropyrimidine and thiourea endowed with sulfonamide moieties as dual EGFRT790M and VEGFR-2 inhibitors: Design, synthesis, docking, and anticancer evaluations.

The effectiveness of a new series of thiopyrimidine and thiourea containing sulfonamides moieties was tested on HCT-116, MCF-7, HepG2, and A549. HepG2 cell line was the one that all the new derivatives affected the most. The greatest potent compounds against the four HepG2, HCT116, MCF-7, and A549 cell lines were 8f and 8g with IC50 = 4.13, 6.64, 5.74, 6.85 µM and 4.09, 4.36, 4.22, 7.25 µM correspondingly. Compound 8g exhibited higher activity than sorafenib against HCT116 and MCF-7 but exhibited lower activity against HepG2 and A549. Moreover, compounds 8f and 8g exhibited higher activities than erlotinib on HepG2, HCT116, and MCF-7 but demonstrated lower activity on A549. The most potent cytotoxic derivatives 6f, 6g, 8c, 8d, 8e, 8f, and 8g were examined on normal VERO cell lines. Our derivatives have low toxicity on VERO cells with IC50 values ranging from 32.05 to 53.15 µM. Additionally, all compounds were assessed for dual VEGFR-2 and EGFRT790M inhibition effects. Compounds 8f and 8g were the most potent derivatives inhibited VEGFR-2 at IC50 value of 0.88 and 0.90 µM, correspondingly. As well, derivatives 8f and 8g could inhibit EGFRT790M demonstrating strongest effects with IC50 = 0.32 and 0.33 µM sequentially. Additionally, the greatest active derivatives ADMET profile was evaluated in relationship with sorafenib and erlotinib as reference agents. The data attained from docking were greatly related to that achieved from the biological testing.

Large-Scale Biogeographical Shifts of Abundance of Antibiotic Resistance Genes and Marine Bacterial Communities as Their Carriers along a Trophic Gradient.

The role of marine environments in the global spread of antibiotic resistance still remains poorly understood, leaving gaps in the One Health-based research framework. Antibiotic resistance genes (ARGs) encoding resistance to five major antibiotic classes, including sulfonamides (sul1, sul2), tetracyclines (tetA, tetB), ß-lactams (blaCTX-M, blaTEMblaVIM), macrolides (ermB, mphA), aminoglycosides (aac3-2), and integrase gene (intl1) were quantified by RT-qPCR, and their distribution was investigated in relation to environmental parameters and the total bacterial community in bottom layer and surface waters of the central Adriatic (Mediterranean), over a 68 km line from the wastewater-impacted estuary to coastal and pristine open sea. Seasonal changes (higher in winter) were observed for antibiotic resistance frequency and the relative abundances of ARGs, which were generally higher in eutrophic coastal areas. In particular, intl1, followed by blaTEM and blaVIM, were strongly associated with anthropogenic influence and Gammaproteobacteria as their predominant carriers. Water column stratification and geographic location had a significant influence on ARGs distribution in the oligotrophic zone, where the bacterial community exhibited a seasonal shift from Gammaproteobacteria in winter to Marine group II in summer.

Methazolamide Reduces the AQP5 mRNA Expression and Immune Cell Migration-A New Potential Drug in Sepsis Therapy?

Sepsis is a life-threatening condition caused by the dysregulated host response to infection. Novel therapeutic options are urgently needed and aquaporin inhibitors could suffice as aquaporin 5 (Aqp5) knockdown provided enhanced sepsis survival in a murine sepsis model. Potential AQP5 inhibitors provide sulfonamides and their derivatives. In this study, we tested the hypothesis that sulfonamides reduce AQP5 expression in different conditions. The impact of sulfonamides on AQP5 expression and immune cell migration was examined in cell lines REH and RAW 264.7 by qPCR, Western blot and migration assay. Subsequently, whether furosemide and methazolamide are capable of reducing AQP5 expression after LPS incubation was investigated in whole blood samples of healthy volunteers. Incubation with methazolamide (10-5 M) and furosemide (10-6 M) reduced AQP5 mRNA and protein expression by about 30% in REH cells. Pre-incubation of the cells with methazolamide reduced cell migration towards SDF1-α compared to non-preincubated cells to control level. Pre-incubation with methazolamide in PBMCs led to a reduction in LPS-induced AQP5 expression compared to control levels, while furosemide failed to reduce it. Methazolamide appears to reduce AQP5 expression and migration of immune cells. However, after LPS administration, the reduction in AQP5 expression by methazolamide is no longer possible. Hence, our study indicates that methazolamide is capable of reducing AQP5 expression and has the potential to be used in sepsis prophylaxis.

A review on carbon-based biowaste and organic polymer materials for sustainable treatment of sulfonamides from pharmaceutical wastewater.

Frequent detection of sulfonamides (SAs) pharmaceuticals in wastewater has necessitated the discovery of suitable technology for their sustainable remediation. Adsorption has been widely investigated due to its effectiveness, simplicity, and availability of various adsorbent materials from natural and artificial sources. This review highlighted the potentials of carbon-based adsorbents derived from agricultural wastes such as lignocellulose, biochar, activated carbon, carbon nanotubes graphene materials as well as organic polymers such as chitosan, molecularly imprinted polymers, metal, and covalent frameworks for SAs removal from wastewater. The promising features of these materials including higher porosity, rich carbon-content, robustness, good stability as well as ease of modification have been emphasized. Thus, the materials have demonstrated excellent performance towards the SAs removal, attributed to their porous nature that provided sufficient active sites for the adsorption of SAs molecules. The modification of physico-chemical features of the materials have been discussed as efficient means for enhancing their adsorption and reusable performance. The article also proposed various interactive mechanisms for the SAs adsorption. Lastly, the prospects and challenges have been highlighted to expand the knowledge gap on the application of the materials for the sustainable removal of the SAs.

Distribution of bacterial community structures and spread of antibiotic resistome at industrially polluted sites of Mini River, Vadodara, Gujarat, India.

The influence of anthropogenic pollution on the distribution of bacterial diversity, antibiotic-resistant bacteria (ARBs), and antibiotic resistance genes (ARGs) was mapped at various geo-tagged sites of Mini River, Vadodara, Gujarat, India. The high-throughput 16S rRNA gene amplicon sequencing analysis revealed a higher relative abundance of Planctomycetota at the polluted sites, compared to the pristine site. Moreover, the relative abundance of Actinobacteriota increased, whereas Chloroflexi decreased in the water samples of polluted sites than the pristine site. The annotation of functional genes in the metagenome samples of Mini River sites indicated the presence of genes involved in the defence mechanisms against bacitracin, aminoglycosides, cephalosporins, chloramphenicol, streptogramin, streptomycin, methicillin, and colicin. The analysis of antibiotic resistome at the polluted sites of Mini River revealed the abundance of sulfonamide, beta-lactam, and aminoglycoside resistance. The presence of pathogens and ARB was significantly higher in water and sediment samples of polluted sites compared to the pristine site. The highest resistance of bacterial populations in the Mini River was recorded against sulfonamide (≥ 7.943 × 103 CFU/mL) and ampicillin (≥ 8.128 × 103 CFU/mL). The real-time PCR-based quantification of ARGs revealed the highest abundance of sulfonamide resistance genes sul1 and sul2 at the polluted sites of the Mini River. Additionally, the antimicrobial resistance genes aac(6')-Ib-Cr and blaTEM were also found abundantly at polluted sites of the Mini River. The findings provide insights into how anthropogenic pollution drives the ARG and ARB distribution in the riverine ecosystem, which may help with the development of antimicrobial resistance mitigation strategies.

Predicting sulfanilamide solubility in the binary mixtures using a reference solvent approach.

BACKGROUND: Solubility is a fundamental physicochemical property of active pharmaceutical ingredients. The optimization of a dissolution medium aims not only to increase solubility and other aspects are to be included such as environmental impact, toxicity degree, availability, and costs. Obtaining comprehensive solubility characteristics of chemical compounds is a non-trivial and demanding process. Therefore, support from theoretical approaches is of practical importance. OBJECTIVES: This study aims to examine the accuracy of the reference solubility approach in the case of sulfanilamide dissolution in a variety of binary solvents. This pharmaceutically active substance has been extensively studied, and a substantial amount of solubility data is available. Unfortunately, using this set of data directly for theoretical modeling is impeded by noticeable inconsistencies in the published solubility data. Hence, this aspect is addressed by data curation using theoretical and experimental confirmations. MATERIAL AND METHODS: In the experimental part of our study, the popular shake-flask method combined with ultraviolet (UV) spectrophotometric measurements was applied for solubility determination. The computational phase utilized the conductor-like screening model for real solvents (COSMO-RS) approach. RESULTS: The analysis of the results of solubility calculations for sulfonamide in binary solvents revealed abnormally high error values for acetone-ethyl acetate mixtures, which were further confirmed with experimental measurements. Additional confirmation was obtained by extending the solubility measurements to a series of homologous acetate esters. CONCLUSIONS: Our study addresses the crucial issue of coherence of solubility data used for many theoretical inquiries, including parameter fitting of semi-empirical models, in-depth thermodynamic interpretations and application of machine learning protocols. The effectiveness of the proposed methodology for dataset curation was demonstrated for sulfanilamide solubility in binary mixtures. This approach enabled not only the formulation of a consistent dataset of sulfanilamide solubility binary solvent mixtures, but also its implementation as a qualitative tool guiding rationale solvent selection for experimental solubility screening.

Lysine-Reactive N-Acyl-N-aryl Sulfonamide Warheads: Improved Reaction Properties and Application in the Covalent Inhibition of an Ibrutinib-Resistant BTK Mutant.

The covalent inhibition of a target protein has gained widespread attention in the field of drug discovery. Most of the current covalent drugs utilize the high reactivity of cysteines toward modest electrophiles. However, there is a growing need for warheads that can target lysine residues to expand the range of covalently druggable proteins and to deal with emerging proteins with mutations resistant to cysteine-targeted covalent drugs. We have recently developed an N-acyl-N-alkyl sulfonamide (NASA) as a lysine-targeted electrophile. Despite its successful application, this NASA warhead suffered from instability in physiological environments, such as serum-containing medium, because of its high intrinsic reactivity. In this study, we sought to modify the structure of the NASA warhead and found that N-acyl-N-aryl sulfonamides (ArNASAs) are promising electrophiles for use in a lysine-targeted covalent inhibition strategy. We prepared a focused library of ArNASA derivatives with diverse structures and reactivity and identified several warhead candidates with suppressed hydrolysis-mediated inactivation and reduced nonspecific reactions with off-target proteins, without sacrificing the reactivity toward the target. These reaction properties enabled the improved covalent inhibition of intracellular heat shock protein 90 (HSP90) in the presence of serum and the development of the first irreversible inhibitor for ibrutinib-resistant Bruton's tyrosine kinase (BTK) bearing the C481S mutation. This study clearly demonstrated the use of a set of ArNASA warheads to create highly potent covalent drugs and highlighted the importance of enriching the current arsenal of lysine-reactive warheads.

Regulating the Growth Rate of Gold Nanobipyramids via a HCl-NADH-Ascorbic Acid System toward a Dual-Channel Multicolor Colorimetric Immunoassay for Simultaneously Screening and Detecting Multiple Sulfonamides.

It is an urgent need to develop simple and high-throughput methods for simultaneously screening and detecting multiple or groups of sulfonamides (SAs) in animal-derived foods since various SAs were alternately used in animal husbandry to avoid generating drug resistance. We herein developed a novel HCl-reduced nicotinamide adenine dinucleotide I (NADH)-ascorbic acid (AA)-mediated gold nanobipyramids (AuNBPs) growth system, which can precisely regulate the growth rate of AuNBPs, to generate two colorful and stable AA-corresponding multicolor signal channels with different sensitivities. Based on the HCl-NADH-AA-mediated AuNBP growth system, we further developed a dual-channel multicolor immunoassay for simultaneously realizing rapid screening and detection of 5 SAs (sulfamethazine, sulfamethoxydiazine, sulfisomidine, sulfamerazine, and sulfamonomethoxine) by using a paper-based analytical device for sensitively and stably reading out the signal and a broad-specificity anti-SAs antibody as a bio-receptor. The developed immunoassay has more color changes, a wider linear range, excellent specificity and stability, and two multicolor signal channels (L-channel and H-channel) with different sensitivities. The H-channel exhibited 7-8 SAs-corresponding color changes and can be used to detect 5 target SAs with a visual detection limit of 0.1-0.5 ng/mL and a spectrometry detection limit of 0.05-0.16 ng/mL. The L-channel exhibited 7-9 SAs-corresponding color changes and can be used to detect 5 target SAs with a visual detection limit of 2.0-6.0 ng/mL and a spectrometry detection limit of 0.40-1.47 ng/mL. The developed immunoassay was successfully used to simultaneously screen and detect low-concentration and high-concentration of target SAs in milk and fish muscle samples with a recovery of 85-110% and an RSD (n = 5) < 8%. The visual detection limit of our immunoassay is much lower than the maximum residue limit of total SAs in edible tissue. All above features make our immunoassay a promising assay for simultaneously realizing the rapid screening and quantitative determination of multiple SA residues in food by bare eye observation. It must be mentioned that our immunoassay may be expended as a general method for the simultaneous visual screening and detection of other drugs using the corresponding antibody as a recognition probe.

Multiplexed SELEX for Sulfonamide Antibiotics Yielding a Group-Specific DNA Aptamer for Biosensors.

The widespread use of sulfonamide (SA) antibiotics in animal husbandry has led to residues of SAs in the environment, causing adverse effects to the ecosystem and a risk of bacterial resistance, which is a potential threat to public health. Therefore, it is highly desirable to develop simple, high-throughput methods that can detect multiple SAs simultaneously. In this study, we isolated aptamers with different specificities based on a multi-SA systematic evolution of ligands by the exponential enrichment (SELEX) strategy using a mixture of sulfadimethoxine (SDM), sulfaquinoxaline (SQX), and sulfamethoxazole (SMZ). Three aptamers were obtained, and one of them showed a similar binding to all tested SAs, with dissociation constant (Kd) ranging from 0.22 to 0.63 µM. For the other two aptamers, one is specific for SQX, and the other is specific for SDM and sulfaclozine. A label-free detection method based on the broad-specificity aptamer was developed for the simultaneous detection of six SAs, with detection of limits ranging from 0.14 to 0.71 µM in a lake water sample. The aptasensor has no binding for other broad-spectrum antibiotics such as ß-lactam antibiotics, quinolones, tetracyclines, and chloramphenicol. This work provides a promising biosensor for rapid, multiresidue, and high-throughput detection of SAs, as well as a shortcut for the preparation of different specific recognition elements required for the detection of broad-spectrum antibiotics.

Investigating sulfonamides - Human serum albumin interactions: A comprehensive approach using multi-spectroscopy, DFT calculations, and molecular docking.

The environmental and health risks associated with sulfonamide antibiotics (SAs) are receiving increasing attention. Through multi-spectroscopy, density functional theory (DFT), and molecular docking, this study investigated the interaction features and mechanisms between six representative SAs and human serum albumin (HSA). Multi-spectroscopy analysis showed that the six SAs had significant binding capabilities with HSA. The order of binding constants at 298 K was as follows: sulfadoxine (SDX): 7.18 × 105 L mol-1 > sulfamethizole (SMT): 6.28 × 105 L mol-1 > sulfamerazine (SMR): 2.70 × 104 L mol-1 > sulfamonomethoxine (SMM): 2.54 × 104 L mol-1 > sulfamethazine (SMZ): 3.06 × 104 L mol-1 > sulfadimethoxine (SDM): 2.50 × 104 L mol-1. During the molecular docking process of the six SAs with HSA, the binding affinity range is from -7.4 kcal mol-1 to -8.6 kcal mol-1. Notably, the docking result of HSA-SDX reached the maximum of -8.6 kcal mol-1, indicating that SDX may possess the highest binding capacity to HSA. HSA-SDX binding, identified as a static quenching and exothermic process, is primarily driven by hydrogen bonds (H bonds) or van der Waals (vdW) interactions. The quenching processes of SMR/SMZ/SMM/SDX/SMT to HSA are a combination of dynamic and static quenching, indicating an endothermic reaction. Hydrophobic interactions are primarily accountable for SMR/SMZ/SMM/SDX/SMT and HSA binding. Competition binding results revealed that the primary HSA-SAs binding sites are in the subdomain IB of the HAS structure, consistent with the results of molecule docking. The correlation analysis based on DFT calculations revealed an inherent relationship between the structural chemical features of SAs and the binding performance of HSA-SAs. The dual descriptor (DD) and the electrophilic Fukui function were found to have a significant relationship (0.71 and -0.71, respectively) with the binding constants of HSA-SAs, predicting the binding performance of SAs and HSA. These insights have substantial scientific value for evaluating the environmental risks of SAs as well as understanding their impact on biological life activities.

The Impact of Patient Age and Corticosteroids in Patients With Sulfonamide Hepatotoxicity.

INTRODUCTION: Sulfonamides are widely used to treat and prevent various bacterial and opportunistic infections. The aim of this study was to describe the clinical presentation and outcomes of a large cohort of patients with sulfonamide hepatotoxicity. METHODS: Between 2004 and 2020, 105 patients with hepatotoxicity attributed to trimethoprim/sulfamethoxazole (TMP-SMZ) (n = 93) or other sulfonamides (n = 12) were enrolled. Available liver biopsies were reviewed by a single hepatopathologist. RESULTS: Among the 93 TMP-SMZ cases, 52% were female, 7.5% younger than 20 years, and the median time to drug-induced liver injury (DILI) onset was 22 days (range: 3-157). Younger patients were significantly more likely to have rash, fever, eosinophilia, and a hepatocellular injury pattern at onset that persisted at the peak of liver injury compared with older patients ( P < 0.05). The 18 (19%) TMP-SMZ patients treated with corticosteroids had more severe liver injury and a higher mortality but a trend toward more rapid normalization of their laboratory abnormalities compared with untreated patients. During follow-up, 6.2% of the TMP-SMZ patients died or underwent liver transplantation. Chronic DILI developed in 20% and was associated with cholestatic injury at onset and higher peak total bilirubin levels. DISCUSSION: Sulfonamide hepatotoxicity is characterized by a short drug latency with frequent hypersensitivity features at onset. Subject age is an important determinant of the laboratory profile at presentation, and patients with cholestasis and higher total bilirubin levels were at increased risk of developing chronic DILI. Corticosteroids may benefit a subgroup of patients with severe injury, but further studies are needed.