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BMC Systems Biology Oct 2013The growing discipline of structural systems pharmacology is applied prospectively in this study to predict pharmacological outcomes of antibacterial compounds in...
BACKGROUND
The growing discipline of structural systems pharmacology is applied prospectively in this study to predict pharmacological outcomes of antibacterial compounds in Escherichia coli K12. This work builds upon previously established methods for structural prediction of ligand binding pockets on protein molecules and utilizes and expands upon the previously developed genome scale model of metabolism integrated with protein structures (GEM-PRO) for E. coli, structurally accounting for protein complexes. Carefully selected case studies are demonstrated to display the potential for this structural systems pharmacology framework in discovery and development of antibacterial compounds.
RESULTS
The prediction framework for antibacterial activity of compounds was validated for a control set of well-studied compounds, recapitulating experimentally-determined protein binding interactions and deleterious growth phenotypes resulting from these interactions. The antibacterial activity of fosfomycin, sulfathiazole, and trimethoprim were accurately predicted, and as a negative control glucose was found to have no predicted antibacterial activity. Previously uncharacterized mechanisms of action were predicted for compounds with known antibacterial properties, including (1-hydroxyheptane-1,1-diyl)bis(phosphonic acid) and cholesteryl oleate. Five candidate inhibitors were predicted for a desirable target protein without any known inhibitors, tryptophan synthase β subunit (TrpB). In addition to the predictions presented, this effort also included significant expansion of the previously developed GEM-PRO to account for physiological assemblies of protein complex structures with activities included in the E. coli K12 metabolic network.
CONCLUSIONS
The structural systems pharmacology framework presented in this study was shown to be effective in the prediction of molecular mechanisms of antibacterial compounds. The study provides a promising proof of principle for such an approach to antibacterial development and raises specific molecular and systemic hypotheses about antibacterials that are amenable to experimental testing. This framework, and perhaps also the specific predictions of antibacterials, is extensible to developing antibacterial treatments for pathogenic E. coli and other bacterial pathogens.
Topics: Anti-Bacterial Agents; Binding Sites; Escherichia coli K12; Escherichia coli Proteins; Genomics; Models, Molecular; Phenotype; Protein Conformation; Systems Biology
PubMed: 24112686
DOI: 10.1186/1752-0509-7-102 -
Pharmaceuticals (Basel, Switzerland) Nov 2022This study constructs a machine learning method to simultaneously analyze the thermodynamic behavior of many polymer-drug systems. The solubility temperature of...
This study constructs a machine learning method to simultaneously analyze the thermodynamic behavior of many polymer-drug systems. The solubility temperature of Acetaminophen, Celecoxib, Chloramphenicol, D-Mannitol, Felodipine, Ibuprofen, Ibuprofen Sodium, Indomethacin, Itraconazole, Naproxen, Nifedipine, Paracetamol, Sulfadiazine, Sulfadimidine, Sulfamerazine, and Sulfathiazole in 1,3-bis[2-pyrrolidone-1-yl] butane, Polyvinyl Acetate, Polyvinylpyrrolidone (PVP), PVP K12, PVP K15, PVP K17, PVP K25, PVP/VA, PVP/VA 335, PVP/VA 535, PVP/VA 635, PVP/VA 735, Soluplus analyzes from a modeling perspective. The least-squares support vector regression (LS-SVR) designs to approximate the solubility temperature of drugs in polymers from polymer and drug types and drug loading in polymers. The structure of this machine learning model is well-tuned by conducting trial and error on the kernel type (i.e., Gaussian, polynomial, and linear) and methods used for adjusting the LS-SVR coefficients (i.e., leave-one-out and 10-fold cross-validation scenarios). Results of the sensitivity analysis showed that the Gaussian kernel and 10-fold cross-validation is the best candidate for developing an LS-SVR for the given task. The built model yielded results consistent with 278 experimental samples reported in the literature. Indeed, the mean absolute relative deviation percent of 8.35 and 7.25 is achieved in the training and testing stages, respectively. The performance on the largest available dataset confirms its applicability. Such a reliable tool is essential for monitoring polymer-drug systems' stability and deliverability, especially for poorly soluble drugs in polymers, which can be further validated by adopting it to an actual implementation in the future.
PubMed: 36422535
DOI: 10.3390/ph15111405 -
Chemosphere Aug 2013Animal production is a leading economic activity in Brazil and antibiotics are widely used. However, the occurrence, behavior, and impacts of antibiotics in Brazilian...
Animal production is a leading economic activity in Brazil and antibiotics are widely used. However, the occurrence, behavior, and impacts of antibiotics in Brazilian soils are still poorly known. We evaluated the sorption behavior of four fluoroquinolones (norfloxacin, ciprofloxacin, danofloxacin, and enrofloxacin) and five sulfonamides (sulfadiazine, sulfachloropyridazine, sulfamethoxazole, sulfadimidine, and sulfathiazole) in 13 Brazilian soils with contrasting physical, chemical, and mineralogical properties. Fluoroquinolone sorption was very high (Kd≥544 L kg(-1)) whereas sulfonamide sorption ranged from low to high (Kd=0.7-70.1 L kg(-1)), consistent with previous reports in the literature. Soil texture and cation exchange capacity were the soil attributes that most affected sorption. Cation exchange was the most important sorption mechanism for the fluoroquinolones in highly weathered tropical soils, although cation bridging and ion pairing could not be ruled out. Hydrophobic partition played an important role in the sorption of the sulfonamides, but sorption was also affected by non-hydrophobic interactions with organic and/or mineral surfaces. Sorption for both compound classes tended to be higher in soils with high Al and Fe oxihydroxide contents, but they were not correlated with Kd values. No direct effect of soil pH was seen. The fluoroquinolones are not expected to leach even in worst-case scenarios (soils rich in sand and poor in organic carbon), whereas soil attributes dictate leaching potential for the sulfonamides.
Topics: Adsorption; Anti-Bacterial Agents; Brazil; Cations; Chromatography, High Pressure Liquid; Environmental Monitoring; Fluoroquinolones; Hydrogen-Ion Concentration; Soil; Soil Pollutants; Sulfonamides
PubMed: 23601127
DOI: 10.1016/j.chemosphere.2013.03.018 -
Combined utilization of metabolic inhibitors to prevent synergistic multi-species biofilm formation.AMB Express Mar 2022Biofilm is ubiquitous in industrial water systems, causing biofouling and leading to heat transfer efficiency decreases. In particular, multi-species living in biofilms...
Biofilm is ubiquitous in industrial water systems, causing biofouling and leading to heat transfer efficiency decreases. In particular, multi-species living in biofilms could boost biomass production and enhance treatment resistance. In this study, a total of 37 bacterial strains were isolated from a cooling tower biofilm where acetic acid and propionic acid were detected as the main carbon sources. These isolates mainly belonged to Proteobacteria and Firmicutes, which occupied more than 80% of the total strains according to the 16S rRNA gene amplicon sequencing. Four species (Acinetobacter sp. CTS3, Corynebacterium sp. CTS5, Providencia sp. CTS12, and Pseudomonas sp. CTS17) were observed co-existing in the synthetic medium. Quantitative comparison of biofilm biomass from mono- and multi-species showed a synergistic effect towards biofilm formation among these four species. Three metabolic inhibitors (sulfathiazole, 3-bromopyruvic acid, and 3-nitropropionic acid) were employed to prevent biofilm formation based on their inhibitory effect on corresponding metabolic pathways. All of them displayed evident inhibition profiles to biofilm formation. Notably, combining these three inhibitors possessed a remarkable ability to block the multi-species biofilm development with lower concentrations, suggesting an enhanced effect appeared in simultaneous use. This study demonstrates that combined utilization of metabolic inhibitors is an alternative strategy to prevent multi-species biofilm formation.
PubMed: 35244796
DOI: 10.1186/s13568-022-01363-4 -
Molecules (Basel, Switzerland) Nov 2022In this study, a simple colorimetric method was established to detect copper ion (Cu), sulfathiazole (ST), and glucose based on the acetylcholinesterase (AChE)-like...
In this study, a simple colorimetric method was established to detect copper ion (Cu), sulfathiazole (ST), and glucose based on the acetylcholinesterase (AChE)-like activity of zeolitic imidazolate framework-8 (ZIF-8). The AChE-like activity of ZIF-8 can hydrolyze acetylthiocholine chloride (ATCh) to thiocholine (TCh), which will further react with 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB) to generate 2-nitro-5-thiobenzoic acid (TNB) that has a maximum absorption peak at 405 nm. The effects of different reaction conditions (buffer pH, the volume of ZIF-8, reaction temperature and time, and ATCh concentration) were investigated. Under the optimized conditions, the value of the Michaelis-Menten constant () is measured to be 0.83 mM, which shows a high affinity toward the substrate (ATCh). Meanwhile, the ZIF-8 has good storage stability, which can maintain more than 80.0% of its initial activity after 30 days of storage at room temperature, and the relative standard deviation (RSD) of batch-to-batch ( = 3) is 5.1%. The linear dependences are obtained based on the AChE-like activity of ZIF-8 for the detection of Cu, ST, and glucose in the ranges of 0.021-1.34 and 5.38-689.66 µM, 43.10-517.24 µM, and 0.0054-1.40 mM, respectively. The limit of detections (LODs) are calculated to be 20.00 nM, 9.25 µM, and 5.24 µM, respectively. Moreover, the sample spiked recoveries of Cu in lake water, ST in milk, and glucose in strawberry samples were measured, and the results are in the range of 98.4-115.4% with the RSD ( = 3) lower than 3.3%. In addition, the method shows high selectivity in the real sample analysis.
Topics: Acetylcholinesterase; Zeolites; Colorimetry; Acetylthiocholine; Glucose
PubMed: 36364318
DOI: 10.3390/molecules27217491 -
The Journal of Experimental Medicine Jan 19431. In vitro experiments were performed with E. coli, using a method designed for the quantitative study of various aspects of sulfonamide resistance. 2. Resistance was...
1. In vitro experiments were performed with E. coli, using a method designed for the quantitative study of various aspects of sulfonamide resistance. 2. Resistance was found to be a gradually developing process, and was demonstrated for all four drugs tested, sulfanilamide, sulfapyridine, sulfathiazole, and sulfadiazine. 3. It was shown that the degree of resistance developed was correlated with the bacteriostatic potency of the sulfonamides, and that organisms resistant to certain bacteriostatic concentrations of one sulfonamide were equally resistant to similar bacteriostatic concentrations of the other sulfonamides. 4. These observations were interpreted as indicating that the development of sulfonamide resistance represents an interaction between the organisms and the one common structural unit of all the sulfonamides, namely, the p-amino nucleus. It is also suggested that this interaction may involve the same enzyme system (or systems) as those concerned in the antagonism of the sulfonamides by para-aminobenzoic acid. 5. The relation of these findings to the broader aspects of sulfonamide resistance is discussed, and it is postulated that, despite reports to the contrary, all organisms susceptible to the bacteriostatic action of the sulfonamides are capable of becoming resistant to all of the sulfonamides.
PubMed: 19871262
DOI: 10.1084/jem.77.1.29 -
Food Chemistry Feb 2018Filter feeders, like mussels and clams, are suitable bioindicators of environmental pollution. These shellfish, when destined for human consumption, undergo a depuration...
Filter feeders, like mussels and clams, are suitable bioindicators of environmental pollution. These shellfish, when destined for human consumption, undergo a depuration step that aims to nullify their pathogenic microorganism load and decrease chemical contamination. Nevertheless, the lack of contamination by drugs may not be guaranteed. Antimicrobials are a class of drugs of particular concern due to the increasing phenomenon of antibiotic resistance. Their use in breeding and aquaculture is a major cause of this. We developed a multiclass method for the HPLC-MS/MS analysis of 29 antimicrobials, validated according to the Commission Decision 2002/657/UE guidelines, and applied it to 50 mussel and 50 clam samples derived from various Food and Agricultural Organisation marine zones. The results obtained, indicate a negligible presence of antibiotics. Just one clam sample showed the presence of oxytetracycline at a concentration slightly higher than the European Union Maximum residue limit set for fish.
Topics: Animals; Anti-Bacterial Agents; Aquaculture; Bivalvia; Tandem Mass Spectrometry
PubMed: 28946257
DOI: 10.1016/j.foodchem.2017.07.072 -
International Journal of Pharmaceutics Nov 2013Developing amorphous pharmaceuticals can be desirable due to advantageous biopharmaceutical properties. Low glass transition temperature (Tg) amorphous drugs can be...
Developing amorphous pharmaceuticals can be desirable due to advantageous biopharmaceutical properties. Low glass transition temperature (Tg) amorphous drugs can be protected from crystallisation by mixing with high Tg excipients, such as polymers, or with salt forms. However, both polymers and salts can enhance the water uptake. The aim of this study was to formulate physico-chemically stable amorphous materials, by co-processing different proportions of sulfathiazole and its sodium salt to produce an optimum ratio, characterised by the best physical stability and lowest hygroscopicity. Both sulfathiazole and salt amorphised upon spray drying. At room temperature, sulfathiazole crystallised within 1h at <5% relative humidity while the salt deliquesced when exposed to ambient humidity conditions. In the case of composite systems, FTIR spectroscopy, thermal and surface analysis suggested interactions with an acid:salt stoichiometry of 1:2. Increasing proportions of salt raised the Tg, enhancing the storage stability, however this was opposed by an enhanced hygroscopicity. The water uptake mechanism within the different amorphous systems, analysed by fitting the water sorption isotherms with the Young and Nelson equation, was dependent on the ratio employed, with the salt and the acid facilitating absorption and adsorption, respectively. Tuning the properties of amorphous salt/acid composites by optimising the ratio appears potentially promising to improve the physical stability of amorphous formulations.
Topics: Acids; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Crystallization; Drug Stability; Powder Diffraction; Salts; Spectroscopy, Fourier Transform Infrared; Sulfathiazole; Sulfathiazoles; Surface Properties; Water; X-Ray Diffraction
PubMed: 23948137
DOI: 10.1016/j.ijpharm.2013.07.076 -
AAPS PharmSciTech Jun 2012Solid-state characterisation of a drug following pharmaceutical processing and upon storage is fundamental to successful dosage form development. The aim of the study...
Solid-state characterisation of a drug following pharmaceutical processing and upon storage is fundamental to successful dosage form development. The aim of the study was to investigate the effects of using different solvents, feed concentrations and spray drier configuration on the solid-state nature of the highly polymorphic model drug, sulfathiazole (ST) and its sodium salt (STNa). The drugs were spray-dried from ethanol, acetone and mixtures of these organic solvents with water. Additionally, STNa was spray-dried from pure water. The physicochemical properties including the physical stability of the spray-dried powders were compared to the unprocessed materials. Spray drying of ST from either acetonic or ethanolic solutions with the spray drier operating in a closed cycle mode yielded crystalline powders. In contrast, the powders obtained from ethanolic solutions with the spray drier operating in an open cycle mode were amorphous. Amorphous ST crystallised to pure form I at ≤35 % relative humidity (RH) or to polymorphic mixtures at higher RH values. The usual crystal habit of form I is needle-like, but spherical particles of this polymorph were generated by spray drying. STNa solutions resulted in an amorphous material upon processing, regardless of the solvent and the spray drier configuration employed. Moisture induced crystallisation of amorphous STNa to a sesquihydrate, whilst crystallisation upon heating gave rise to a new anhydrous polymorph. This study indicated that control of processing and storage parameters can be exploited to produce drugs with a specific/desired solid-state nature.
Topics: Acetone; Anti-Infective Agents; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Crystallization; Crystallography, X-Ray; Drug Storage; Ethanol; Humidity; Microscopy, Electron, Scanning; Powder Diffraction; Powders; Solubility; Solvents; Sulfathiazole; Sulfathiazoles; Technology, Pharmaceutical; Water
PubMed: 22549223
DOI: 10.1208/s12249-012-9792-5 -
Journal of Bacteriology Aug 1964Howarth, S. (University of Otago, Dunedin, New Zealand), and M. D. Dedman. Pigmentation variants of Pseudomonas aeruginosa. J. Bacteriol. 88:273-278. 1964.-Pigmentation...
Howarth, S. (University of Otago, Dunedin, New Zealand), and M. D. Dedman. Pigmentation variants of Pseudomonas aeruginosa. J. Bacteriol. 88:273-278. 1964.-Pigmentation variants were isolated from Pseudomonas aeruginosa strain 1, including both FP(+) and FP(-) sublines, and strain 78 by growth with sulfathiazole. The changes were from the normal yellow-green color to brown and nonpigmented variants. Brown variants arising from strain 1 were studied in most detail, and were found to occur as spontaneous mutants in the normal population with a frequency of about 10(-7). These variants have other altered characteristics; notably, they show a change to a smooth colony morphology and resistance to the virulent bacteriophage E79. When grown in the presence of sulfathiazole, pigmentation variants have a selective growth advantage, which would account for their presence in unusually high numbers in populations surviving sulfathiazole treatment.
Topics: Bacteriophages; New Zealand; Pharmacology; Pigmentation; Pigments, Biological; Pseudomonas; Pseudomonas aeruginosa; Research; Sulfathiazole; Sulfathiazoles
PubMed: 14203341
DOI: 10.1128/jb.88.2.273-278.1964