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Antimicrobial Agents and Chemotherapy Aug 1995Forty-four sulfa drugs were screened against crude preparations of recombinant Pneumocystis carinii dihydropteroate synthetase. The apparent Michaelis-Menten constants... (Comparative Study)
Comparative Study
Forty-four sulfa drugs were screened against crude preparations of recombinant Pneumocystis carinii dihydropteroate synthetase. The apparent Michaelis-Menten constants (Km) for p-aminobenzoic acid and 7,8-dihydro-6-hydroxymethylpterin pyrophosphate were 0.34 +/- 0.02 and 2.50 +/- 0.71 microM, respectively. Several sulfa drugs, including sulfathiazole, sulfachlorpyridazine, sulfamethoxypyridazine, and sulfathiourea, inhibited dihydropteroate synthetase approximately as well as sulfamethoxazole, as determined by the concentrations which cause 50% inhibition and/or by Ki. For all sulfones and sulfonamides tested, unsubstituted p-amino groups were necessary for activity, and sulfonamides containing an N1-heterocyclic substituent were found to be the most effective inhibitors. Folate biosynthesis in isolated intact P. carinii was approximately equally sensitive to inhibition by sulfamethoxazole, sulfachlorpyridazine, sulfamethoxypyridazine, sulfisoxazole, and sulfathiazole. Two of these drugs, sulfamethoxypyridazine and sulfisoxazole, are known to be less toxic than sulfamethoxazole and should be further evaluated for the treatment of P. carinii pneumonia.
Topics: Animals; Anti-Infective Agents; Dihydropteroate Synthase; Folic Acid; Kinetics; Lung; Male; Pneumocystis; Pneumocystis Infections; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Structure-Activity Relationship; Sulfonamides
PubMed: 7486915
DOI: 10.1128/AAC.39.8.1756 -
Water, Air, and Soil Pollution 2021Sulfonamides (SAs) including sulfamethoxypyridazine (SMP) are regarded as a new type of persistent pollutant at present due to their abuse. In this work, the direct...
UNLABELLED
Sulfonamides (SAs) including sulfamethoxypyridazine (SMP) are regarded as a new type of persistent pollutant at present due to their abuse. In this work, the direct photodegradation behavior of 11 SAs under simulated sunlight was first investigated, and the results indicated that the direct photolysis of SMP is the slowest among these SAs. Then the oxidation degradation of SMP in UV/Co(II)/peroxymonosulfate (PMS) system was systematically explored. Up to 95.2% removal of 0.071 mM SMP was observed after 20 min of reaction under the optimal condition with a molar ratio of 1:150:5 between SMP, PMS, and Co(II). The effects of some coexisting anions on degradation of SMP were investigated. It was found that Cl and high concentrations of CO and HCO have a significant inhibitory effect, while HPO has only a slight positive effect. Radical scavenger experiments indicated that hydroxyl radicals (HO) are prevailing active species responsible for SMP removal in UV/Co(II)/PMS system. The degradation of SMP in UV/Co(II)/PMS system was accomplished mainly by hydroxylation of the aromatic ring, extrusion of SO, oxidation of NH group, and N - S bond cleavage. Eight intermediates for SMP degradation were identified, and their toxicities to aquatic organisms were predicted by using the ECOSAR program based on the structure - activity relationships (SARs), which suggested that the chronic toxicities of SMP and its degradation intermediates are more significant than their acute toxicities. The present research indicates that UV/Co(II)/PMS system is applicable for SMP degradation in aqueous solutions and may be helpful to understand the transformation behavior of SAs.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s11270-021-05351-5.
PubMed: 34611370
DOI: 10.1007/s11270-021-05351-5 -
Journal of Analytical Methods in... 2018A multiresidue method for detecting and quantifying sulfonamides (sulfapyridine, sulfamerazine, sulfathiazole, sulfamethazine, sulfadimethoxine, sulfamethoxazole, and...
Multiresidue Method for Quantification of Sulfonamides and Trimethoprim in Tilapia Fillet by Liquid Chromatography Coupled to Quadrupole Time-of-Flight Mass Spectrometry Using QuEChERS for Sample Preparation.
A multiresidue method for detecting and quantifying sulfonamides (sulfapyridine, sulfamerazine, sulfathiazole, sulfamethazine, sulfadimethoxine, sulfamethoxazole, and sulfamethoxypyridazine) and trimethoprim in tilapia fillet () using liquid chromatography coupled to mass spectrometry was developed and validated. The sample preparation was optimized using the QuEChERS approach. The chromatographic separation was performed using a C18 column and 0.1% formic acid in water and acetonitrile as the mobile phase in the isocratic elution mode. Method validation was performed based on the Commission Decision 2002/657/EC and Brazilian guideline. The validation parameters evaluated were linearity ( ≥ 0.99); limits of detection (LOD) and quantification (LOQ), 1 ng·g and 5 ng·g, respectively; intraday and interdays precision (CV lower than 19.4%). The decision limit (CC 102.6-120.0 ng·g and 70 ng·g for sulfonamides and trimethoprim, respectively) and detection capability (CC 111.7-140.1 ng·g and 89.9 ng·g for sulfonamides and trimethoprim, respectively) were determined. Analyses of tilapia fillet samples from fish exposed to sulfamethazine through feed (incurred samples) were conducted in order to evaluate the method. This new method was demonstrated to be fast, sensitive, and suitable for monitoring sulfonamides and trimethoprim in tilapia fillet in health surveillance programs, as well as to be used in pharmacokinetics and residue depletion studies.
PubMed: 29686929
DOI: 10.1155/2018/4506754 -
Antibiotics (Basel, Switzerland) Jun 2021Many of the infectious diseases that affect livestock have bacteria as etiological agents. Thus, therapy is based on antimicrobials that leave the animal's tissues...
Many of the infectious diseases that affect livestock have bacteria as etiological agents. Thus, therapy is based on antimicrobials that leave the animal's tissues mainly via urine, reaching the environment through slurry and waste water. Once there, antimicrobial residues may lead to antibacterial resistance as well as toxicity for plants, animals, or humans. Hence, the objective was to describe the rate of antimicrobial excretion in urine in order to select the most appropriate molecule while reducing harmful effects. Thus, 62 pigs were treated with sulfamethoxypyridazine, oxytetracycline, and enrofloxacin. Urine was collected through the withdrawal period and analysed via LC-MS/MS. Oxytetracycline had the slowest rate of degradation (a half-life time of 4.18 days) and the most extended elimination period in urine (over 2 months), followed by enrofloxacin (a half-life time of 1.48 days, total urine elimination in ca. 3 weeks) and sulfamethoxypyridazine (a half-life time of 0.49 days, total urine elimination in ca. 1 week). Bacterial sensitivity and recommendations for responsible use are limiting when selecting the treatment. Nevertheless, with similar effectiveness, sulfamethoxypyridazine would be the choice, as waste treatment would only need to be implemented for 1 week after treatment. Thus, more in-depth knowledge regarding antibacterial elimination would improve resource management, while protecting animals and consumers' health.
PubMed: 34201627
DOI: 10.3390/antibiotics10070762 -
Materials (Basel, Switzerland) Dec 2021The comparison of the efficiency of the commercially available photocatalysts, TiO and ZnO, irradiated with 365 nm and 398 nm light, is presented for the removal of two...
The comparison of the efficiency of the commercially available photocatalysts, TiO and ZnO, irradiated with 365 nm and 398 nm light, is presented for the removal of two antibiotics, sulfamethazine (SMT) and sulfamethoxypyridazine (SMP). The OH formation rate was compared using coumarin, and higher efficiency was proved for TiO than ZnO, while for 1,4-benzoquinone in O-free suspensions, the higher contribution of the photogenerated electrons to the conversion was observed for ZnO than TiO, especially at 398 nm irradiation. An extremely fast transformation and high quantum yield of SMP in the TiO/LED process were observed. The transformation was fast in both O containing and O-free suspensions and takes place via desulfonation, while in other cases, mainly hydroxylated products form. The effect of reaction parameters (methanol, dissolved O content, HCO and Cl) confirmed that a quite rarely observed energy transfer between the excited state P25 and SMP might be responsible for this unique behavior. In our opinion, these results highlight that "non-conventional" mechanisms could occur even in the case of the well-known TiO photocatalyst, and the effect of wavelength is also worth investigating.
PubMed: 35009197
DOI: 10.3390/ma15010049 -
Antibiotics (Basel, Switzerland) Apr 2020The introduction of antimicrobial residues in the food chain has a significant impact on human health. An innovative solution to avoid their presence in meat is the...
The introduction of antimicrobial residues in the food chain has a significant impact on human health. An innovative solution to avoid their presence in meat is the adaptation of current control methods for use with in vivo matrixes. Thus, the aim was to obtain paired blood and muscle samples from pigs treated with some of the main antimicrobials currently used in veterinary medicine (oxytetracycline, sulfamethoxypyridazine, enrofloxacin, amoxicillin), and to compare their rate of depletion in both matrixes. Antimicrobial concentrations in paired samples of blood and muscle were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS) or high performance liquid chromatography with fluorescence detection (HPLC-FLD). A comparison between values obtained in muscle and blood showed a similar distribution in both matrixes for oxytetracycline; for sulfamethoxypyridazine, a similar decrease rate but a concentration three times higher in blood compared to muscle was found; for enrofloxacin, we found significant differences in the rate of depletion, with similar antimicrobial concentrations in both matrixes with values close to the maximum residue limit (MRL) and higher amounts in muscle for values that lay considerably over the MRL. Conversely, amoxicillin depletion was so rapid that its appearance in carcasses does not seem to pose a risk. Therefore, blood would be a feasible matrix for the development of new in vivo tests.
PubMed: 32290542
DOI: 10.3390/antibiotics9040175 -
EBioMedicine Apr 2019Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a...
BACKGROUND
Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time- and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment.
METHODS
In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with >1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions.
FINDINGS
We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line.
INTERPRETATION
Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.
Topics: Cell Line, Tumor; Cell Survival; Drug Discovery; Drug Repositioning; Gene Expression Profiling; Genes, Reporter; Genome, Human; Genomics; Humans; Male; Metabolic Networks and Pathways; Metabolomics; Piperidines; Prostatic Neoplasms; Proteome; Proteomics
PubMed: 30905848
DOI: 10.1016/j.ebiom.2019.03.009 -
Frontiers in Microbiology 2016Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for...
Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even when pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.
PubMed: 27242757
DOI: 10.3389/fmicb.2016.00743 -
Frontiers in Plant Science 2012Plant activators are agrochemicals that protect crops from diseases by activating the plant immune system. To isolate lead compounds for use as practical plant...
Plant activators are agrochemicals that protect crops from diseases by activating the plant immune system. To isolate lead compounds for use as practical plant activators, we screened two different chemical libraries composed of various bioactive substances by using an established screening procedure that can selectively identify immune-priming compounds. We identified and characterized a group of sulfonamide compounds - sulfameter, sulfamethoxypyridazine, sulfabenzamide, and sulfachloropyridazine - among the various isolated candidate molecules. These sulfonamide compounds enhanced the avirulent Pseudomonas-induced cell death of Arabidopsis suspension cell cultures and increased disease resistance in Arabidopsis plants against both avirulent and virulent strains of the bacterium. These compounds did not prevent the growth of pathogenic bacteria in minimal liquid media at 200 μM. They also did not induce the expression of defense-related genes in Arabidopsis seedlings, at least not at 24 and 48 h after treatment, suggesting that they do not act as salicylic acid analogs. In addition, although sulfonamides are known to be folate biosynthesis inhibitors, the application of folate did not restore the potentiation effects of the sulfonamides on pathogen-induced cell death. Our data suggest that sulfonamides potentiate Arabidopsis disease resistance by their novel chemical properties.
PubMed: 23118736
DOI: 10.3389/fpls.2012.00245 -
Epidemiology and Infection Aug 2008To determine prevalence, serotype diversity and antimicrobial resistance of Salmonella in healthy pigs, faecal samples from 6771 pigs on 73 farms collected during...
To determine prevalence, serotype diversity and antimicrobial resistance of Salmonella in healthy pigs, faecal samples from 6771 pigs on 73 farms collected during 1998-1999 and 2004-2005 were examined. Salmonella isolates were serotyped and tested for susceptibility to 22 antimicrobials: benzylpenicillin, ampicillin, amoxicillin, cefazolin, cephaloridine, gentamicin, kanamycin, streptomycin, fradiomycin, colistin, tetracycline, chlortetracycline, oxytetracycline, chloramphenicol, thiamphenicol, sulfadimethoxine, sulfamethoxazole, sulfamethoxypyridazine, trimethoprim, sulfamethoxazole/trimethoprim, norfloxacin and ofloxacin. Farm-level and pig-level Salmonella prevalences were 35.5% and 2.2% in 1998-1999, and 35.7% and 3.3% in 2004-2005. Prevalence by growth stage was 2.4% for sows, 3.3% for weaned pigs, 2.7% for fattening pigs and 3.8% for finishing pigs. The predominant serotypes identified were Agona (28.4%), Typhimurium (17.9%) and Infantis (16.4%) in 1998-1999, and Typhimurium (32.5%), Anatum (24.6%) and Infantis (13.5%) in 2004-2005. Compared with the 1998-1999 isolates, the 2004-2005 isolates showed significantly higher rates of resistance to all the antimicrobials except tetracyclines (P<0.01 to P<0.05) and resistance to 2 antimicrobials [19.4% (13/67) vs. 39.7% (50/126), P<0.01]. This study provides national estimates of Salmonella prevalence in healthy pigs of different growth stages in Japan.
Topics: Animals; Bacterial Typing Techniques; Chi-Square Distribution; Colony Count, Microbial; Disease Reservoirs; Drug Resistance, Bacterial; Feces; Japan; Microbial Sensitivity Tests; Prevalence; Salmonella Infections, Animal; Salmonella enterica; Serotyping; Swine; Swine Diseases
PubMed: 17961277
DOI: 10.1017/S0950268807009570