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1.
Water Sci Technol ; 87(11): 2597-2606, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37318913

ABSTRACT

Tylosin is a commonly used antibiotic in animal medicine. However, it remains unclear how tylosin impacts the broader ecosystem once the host animal has excreted it. One of the main concerns is that it can lead to the development of antibiotic resistance. Therefore, there exists a need to develop systems that remove tylosin from the environment. Utilizing UV irradiation to destroy pathogens is one technique often deployed by scientists and engineers. However, for light-based techniques to be efficient, it is necessary to understand the spectral properties of the material being removed. Steady-state spectroscopy and density functional theory were used to analyze the electronic transitions of tylosin responsible for its strong absorbance in the mid-UV region. It was observed that the absorbance peak of tylosin stems from two transitions in the conjugated region of the molecule. Moreover, these transitions stem from an electronegative region of the molecule, which would allow them to be manipulated by changing solvent polarity. Finally, a polariton model has been proposed, which can be used to initiate the photodegradation of tylosin without the need for direct irradiation of the molecule with UV-B light.


Subject(s)
Ecosystem , Tylosin , Animals , Tylosin/chemistry , Anti-Bacterial Agents/chemistry , Spectrum Analysis , Ultraviolet Rays
2.
Molecules ; 27(21)2022 Oct 26.
Article in English | MEDLINE | ID: mdl-36364103

ABSTRACT

Although many antibiotics are active against Gram-positive bacteria, fewer also show activity against Gram-negative bacteria. Here, we present a combination of in silico (electron ion-interaction potential, molecular docking, ADMET), NMR, and microbiological investigations of selected macrolides (14-membered, 15-membered, and 16-membered), aiming to discover the pattern of design for macrolides active against Gram-negative bacteria. Although the conformational studies of 14-membered and 15-membered macrolides are abundant in the literature, 16-membered macrolides, and their most prominent representative tylosin A, have received relatively little research attention. We therefore report the complete 1H and 13C NMR assignment of tylosin A in deuterated chloroform, as well as its 3D solution structure determined through molecular modelling (conformational search) and 2D ROESY NMR. Additionally, due to the degradation of tylosin A in deuterated chloroform, other species were also detected in 1D and 2D NMR spectra. We additionally studied the anti-bacterial activity of tylosin A and B against selected Gram-positive and Gram-negative bacteria.


Subject(s)
Macrolides , Tylosin , Tylosin/pharmacology , Tylosin/chemistry , Macrolides/chemistry , Anti-Bacterial Agents/chemistry , Chloroform , Escherichia coli/metabolism , Gram-Positive Bacteria/metabolism , Molecular Docking Simulation , Gram-Negative Bacteria/metabolism
3.
J Hazard Mater ; 440: 129716, 2022 10 15.
Article in English | MEDLINE | ID: mdl-35952431

ABSTRACT

Microbial bioremediation offers a solution to the problem of residual antibiotics in wastewater associated with animal farms. Efficient degradation of antibiotic residues depends upon the genetic make-up of microbial degraders, which requires a comprehensive understanding of the degradation mechanisms. In this study, a novel, efficient tylosin (TYL)-degrading bacterium, Providencia stuartii TYL-Y13 (Y13) was isolated, which could completely degrade 100 mg/L TYL within 15 h under optimal operating conditions at 40 â„ƒ, pH 7.0 %, and 1 % (v/v) bacterial inoculation rate. Whole genome sequencing revealed that strain Y13 consists of a circular chromosome and two plasmids. A new biodegradation pathway of TYL including desugarification, hydrolysis, and reduction reactions was proposed through the analysis of biodegradation products. It was demonstrated that strain Y13 gradually decreased the biotoxicity of TYL and its metabolites based on the results of the ecological structural activity relationships (ECOSAR) model analysis and toxicity assessment. Moreover, Y13 promoted the reduction of the target macrolide resistance genes in wastewater and disappeared within 84 h. These results shed new light on the mechanism of TYL biodegradation and better utilization of microbes to remediate TYL contamination.


Subject(s)
Tylosin , Wastewater , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biodegradation, Environmental , Drug Resistance, Bacterial , Genetic Background , Macrolides , Providencia , Risk Assessment , Swine , Tylosin/chemistry
4.
J Chromatogr A ; 1642: 461969, 2021 Apr 12.
Article in English | MEDLINE | ID: mdl-33735645

ABSTRACT

In this research, in order to separate and purify diol-containing macrolide antibiotics, like tylosin, from complex biological samples, molecularly imprinted polymer (MIP) based on boronate affinity for tylosin was synthesized by using precipitation polymerization method with 4-vinylphenylboronic acid (VPBA) and dimethyl aminoethyl methacrylate (DMAEMA) as pH-responsive functional monomers, and N,N'-methylene bisacrylamide (MBAA)/ ethylene glycol dimethacrylate (EGDMA) as the co-crosslinkers that balance the hydrophobicity of the MIP. The synthesized tylosin-MIP had the advantages of high adsorption capacity (120 mg/g), fast pH-responsiveness responsible for the accessibility of imprinted cavities, and high selectivity coefficient towards tylosin versus its analogues (2.8 versus spiramycin, 7.3 versus desmycosin) in an aqueous environment. The mechanism of boronate affinity between tylosin and VPBA in the form of charged hydrogen bonding was analyzed via density functional theory (DFT). MIPs were used to successfully separate diol-containing macrolides through molecularly imprinted solid phase extraction (MISPE). The results show that MIPs prepared in this method have a good application prospect in the separation and purification of the diol-containing macrolide antibiotics.


Subject(s)
Anti-Bacterial Agents/analysis , Boronic Acids/chemistry , Hydrophobic and Hydrophilic Interactions , Macrolides/analysis , Molecular Imprinting , Molecularly Imprinted Polymers/chemical synthesis , Acrylamides/chemistry , Adsorption , Chromatography, High Pressure Liquid , Cross-Linking Reagents/chemistry , Density Functional Theory , Ethylamines/chemistry , Hydrogen Bonding , Hydrogen-Ion Concentration , Methacrylates/chemistry , Molecular Dynamics Simulation , Solid Phase Extraction , Temperature , Tylosin/analysis , Tylosin/chemistry
5.
Ecotoxicol Environ Saf ; 207: 111255, 2021 Jan 01.
Article in English | MEDLINE | ID: mdl-32905936

ABSTRACT

Microplastics are widespread in the environment and might transport readily by ocean currents, wind and atmospheric deposition. Simultaneously, antibiotics and heavy metals could often be detected in the environment. They are both positively charged, it is necessary to clarify the interactions of these pollutants with microplastics when they were coexist. In this study, the most commonly used polystyrene (PS) was selected as a representative microplastic. This study investigated the effect of Cd(II) on the sorption of TYL by PS in different coexistence systems. The results showed that: in the composite system, when TYL and Cd(II) coexist, the presence of Cd(II) could inhibit the sorption of TYL by PS, and the inhibitory effect increases with the increase of the concentration of Cd(II), indicating that competitive sorption dominates the sorption. When PS adsorbed Cd(II) first and then adsorbed TYL, the presence of Cd(II) was conducive to the sorption of TYL, and the sorption strengthened with the increase of Cd(II) concentration, indicating that the complexation between TYL and Cd(II) enhanced the sorption of TYL. In addition, initial pH values and ionic strength were essential in the sorption process. Therefore, this study could provide an important basis for evaluating the environmental behavior and ecological risk of microplastics in the process of compound pollution.


Subject(s)
Microplastics/chemistry , Polystyrenes/chemistry , Tylosin/chemistry , Adsorption , Anti-Bacterial Agents/chemistry , Cadmium , Environmental Pollutants , Metals, Heavy , Osmolar Concentration , Plastics/chemistry
6.
Molecules ; 25(14)2020 Jul 17.
Article in English | MEDLINE | ID: mdl-32709030

ABSTRACT

Antibiotics are active substances frequently used to treat and prevent diseases in animal husbandry, especially in swine and poultry farms. The use of manure as a fertilizer may lead to the dispersion of antibiotic residue into the environment and consequently the development of antibiotic-resistant bacteria. Most pharmaceutical active ingredients are excreted after administration, in some cases up to 90% of the consumed dose can be found in the feces and/or urine as parent compound. Therefore, due to antibiotic metabolism their residues can be easily detected in manure. This article describes a method for simultaneous analysis of ciprofloxacin, chlortetracycline, doxycycline, enrofloxacin, lincomycin, oxytetracycline, tetracycline, tiamulin, trimethoprim and tylosin in feces, liquid manure and digestate. Antibiotics were extracted from the different matrices with McIlvaine-Na2EDTA buffer solution and the extract was purified by the use two techniques: d-SPE and SPE (Strata-X-CW cartridges) and final eluent was analyzed by LC-MS and LC-MS/MS. The European Commission Decision 2002/657/EC was followed to conduct the validation of the method. Recoveries obtained from spiked pig and poultry feces and liquid manures samples ranged from 63% to 93% depending on analytes. The analysis of 70 samples (feces, liquid manure and digestate) revealed that 18 samples were positive for the presence of doxycycline, oxytetracycline, tetracycline, chlortetracycline, enrofloxacin, tiamulin and lincomycin. The results obtained in the presented study demonstrated that animal feces can be used as a non-invasive method detection antibiotic usage in animal production.


Subject(s)
Anti-Bacterial Agents/isolation & purification , Feces/chemistry , Animals , Anti-Bacterial Agents/therapeutic use , Chlortetracycline/chemistry , Chlortetracycline/isolation & purification , Chlortetracycline/therapeutic use , Chromatography, Liquid , Doxycycline/chemistry , Doxycycline/isolation & purification , Doxycycline/therapeutic use , Livestock , Mass Spectrometry , Oxytetracycline/chemistry , Oxytetracycline/isolation & purification , Oxytetracycline/therapeutic use , Poultry , Swine , Tetracycline/chemistry , Tetracycline/isolation & purification , Tetracycline/therapeutic use , Tylosin/chemistry , Tylosin/isolation & purification , Tylosin/therapeutic use
7.
J Vet Pharmacol Ther ; 43(4): 347-354, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32133660

ABSTRACT

The objectives of this study were to compare the plasma and lung tissue pharmacokinetics of tilmicosin in healthy and Mycoplasma gallisepticum-infected chickens. Tilmicosin was orally administered at 4, 7.5 and 10 mg/kg body weight (b.w) for the infected and 7.5 mg/kg b.w for the uninfected control group. We found no significant differences in plasma tilmicosin pharmacokinetics between diseased and healthy control chickens. In contrast, the lung tissues in M. gallisepticum-infected chickens displayed a t1/2 (elimination half-life) 1.76 times longer than for healthy chickens. The Cmax (the maximum concentration of drug in samples) of tilmicosin in M. gallisepticum-infected chickens was lower than for controls at 7.5 mg/kg b.w (p < .05), and the AUCinf (the area under the concentration-time curve from time 0 extrapolated to infinity) in infected chickens was higher than for the healthy chickens (p < .05). The mean residence time of tilmicosin in infected chickens was also higher than the healthy chickens. These results indicated that the lungs of healthy chickens had greater absorption of tilmicosin than the infected chickens, and the rate of elimination of tilmicosin from infected lungs was slower.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Chickens/metabolism , Mycoplasma Infections/veterinary , Mycoplasma gallisepticum , Poultry Diseases/microbiology , Tylosin/analogs & derivatives , Administration, Oral , Animals , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Area Under Curve , Chickens/blood , Half-Life , Lung/chemistry , Mycoplasma Infections/blood , Mycoplasma Infections/drug therapy , Mycoplasma Infections/microbiology , Poultry Diseases/blood , Poultry Diseases/drug therapy , Random Allocation , Tylosin/administration & dosage , Tylosin/chemistry , Tylosin/pharmacokinetics , Tylosin/therapeutic use
8.
Molecules ; 25(2)2020 Jan 13.
Article in English | MEDLINE | ID: mdl-31941074

ABSTRACT

This study aimed to develop nanostructured lipid carriers (NLCs) for improved oral absorption of tilmicosin (TMS) in broilers. Thus, palmitic acid, lauric acid, and stearic acid were selected as solid lipids to formulate TMS-pNLCs, TMS-lNLCs, and TMS-sNLCs, respectively. They showed similar physicochemical properties and meanwhile possessed excellent storage and gastrointestinal stability. The TMS interacted with the lipid matrix and was encapsulated efficiently in NLCs in an amorphous structure. NLCs could enhance oral absorption of TMS compared to 10% tilmicosin phosphate solution in broilers, among which the TMS-sNLCs were the most efficient drug delivery carriers, with a relative oral bioavailability of 203.55%. NLCs could inhibit the efflux of P-glycoprotein (P-pg) toward TMS, which may be involved with improved oral absorption. Taken together, these types of solid lipids influenced the enhanced level of NLCs toward oral bioavailability of TMS, and the sNLCs proved to be the most promising oral delivery carriers of TMS.


Subject(s)
Drug Carriers , Fatty Acids , Nanoparticles , Tylosin/analogs & derivatives , Administration, Oral , Animals , Chickens , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Carriers/pharmacology , Fatty Acids/chemistry , Fatty Acids/pharmacokinetics , Fatty Acids/pharmacology , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Tylosin/chemistry , Tylosin/pharmacokinetics , Tylosin/pharmacology
9.
Article in English | MEDLINE | ID: mdl-31917648

ABSTRACT

Tylosin A is a macrolide antibiotic used in beekeeping. The aim of the study was to characterise the behaviour of tylosin A in honey after heating and during storage, and to identify its degradation products using a non-targeted approach. In addition, the possibility of a semi-quantification of tylosin B using tylosin A was assessed as a case study for the semi-quantification of degradation products using the parent compounds. The results showed significant degradation of tylosin A in aqueous solution (~96%) as well as in spiked and incurred honey dissolved in water (~50% and ~29%, respectively) after heating at 100°C for 90 min. However, at a lower heating temperature of 70°C, degradation was only observed in water (~31%). When stored at room temperature (27°C) for one year, tylosin A degraded significantly (~47%) in an incurred honey sample. Tylosin B, the only reported degradation product of tylosin A in honey so far, increased significantly in aqueous solution under all treatments, but it only increased in spiked water-honey mixture after heating at 100°C. Two new degradation products, namely 5-O-mycaminosyltylonolide (OMT) and lactenocin, were tentatively identified in water and spiked honey after heating at 100°C. The results of the present study reinforce the conclusion that relying only on the water model or spiked food matrix is not sufficient to understand the thermal degradation of antibiotics in food matrices. Finally, a semi-quantification of tylosin B with a relative error of 20% in an incurred honey sample was possible using the response factor of tylosin A, its parent compound. The results of this study prove that a semi-quantification using the parent compound to quantify its degradation compound can provide satisfactory results, but this will be analyte-dependent.


Subject(s)
Anti-Bacterial Agents/chemistry , Food Safety , Honey/analysis , Tylosin/chemistry , Water/analysis , Hot Temperature
10.
Pak J Pharm Sci ; 33(5): 2143-2151, 2020 Sep.
Article in English | MEDLINE | ID: mdl-33824123

ABSTRACT

The objective of this study is to mask the extremely bitter taste of tilmicosin, and the tilmicosin-resin complex (DRC) microsphere were prepared by entrapping tilmicosin into resins (Tulsion® 339 and Eudragit® RS/ RL 100) for further pharmacokinetics study in rat. The DRC was characterized by FTIR and X-ray diffraction, and the microsphere containing DRC and Eudragit® RS/RL 100 were characterized by scanning electron microscopy (SEM). The rats were orally administrated with tilmicosin phosphate (10 mg/kg) and the microsphere containing the same dose of tilmicosin, respectively. These microspheres do not taste bitter and the kinetics study suggests that the drug released from microsphere meet the first order kinetics (r = 0.9911). The experimental results showed that T½ and Tmax of microsphere were much longer than tilmicosin phosphate, which indicates that the oral microsphere can be a promising long-active formulation for taste masking of tilmicosin.


Subject(s)
Acrylic Resins/chemistry , Drug Carriers , Tylosin/analogs & derivatives , Administration, Oral , Animals , Biological Availability , Delayed-Action Preparations , Drug Compounding , Drug Liberation , Male , Microspheres , Particle Size , Rats, Sprague-Dawley , Solubility , Taste , Tylosin/administration & dosage , Tylosin/blood , Tylosin/chemistry , Tylosin/pharmacokinetics
11.
Colloids Surf B Biointerfaces ; 183: 110431, 2019 Nov 01.
Article in English | MEDLINE | ID: mdl-31421405

ABSTRACT

Extracellular DNA (eDNA), which is commonly detected in aquatic and terrestrial environments, may be involved in gene transfer, increases in genetic diversity, and evolution. However, it has been reported that some small organic molecules or heavy metal ions can influence the transformation of DNA and even destroy its structure. We previously found that tylosin (TYL, a kind of antibiotic) is adsorbed onto salmon sperm DNA in a mixed solution. However, it is not clear whether this antibiotic affects the structure of DNA, and the mechanism of their interaction needs to be clarified. Therefore, we investigated the adsorption of TYL on different concentrations of salmon sperm DNA using agarose gel electrophoresis, ultraviolet-visible (UV-vis) spectroscopy, fluorescence spectroscopy, and surface enhanced Raman spectroscopy (SERS) to elucidate the interaction mechanism between TYL and DNA. The results showed that the adsorption of TYL decreased with increased concentrations of DNA. The electrophoresis band of pristine DNA was at 5000 bps. The brightness of the DNA band decreased with the TYL concentration and their incubation time. As the concentration of TYL increased, the fluorescence absorption intensity of DNA decreased significantly. Redshift and hyperchromicity were observed in the UV-vis adsorption spectrum with the presence of TYL in DNA solution, and they weakened as the DNA concentration increased. The Raman spectrum intensities of characteristic peaks in the mixed solution were weaker than that of pure TYL solution, and the peak intensity increased with increasing DNA concentration. Even a part of TYL characteristic peaks disappeared in the mixed solution. These results indicated that the pyran and macrolide of TYL might intercalate into the base pair plane of DNA. In addition, electrostatic attraction between TYL and DNA and interactions among TYL molecules may also play a role in the interaction mechanism. However, the double helix structure of DNA was not subject to the interaction of TYL.


Subject(s)
DNA/chemistry , Nucleic Acid Conformation , Spectrum Analysis/methods , Tylosin/chemistry , Adsorption , Animals , DNA/metabolism , Hydrogen-Ion Concentration , Male , Models, Molecular , Molecular Structure , Salmon , Spectrum Analysis, Raman/methods , Spermatozoa/metabolism , Static Electricity , Tylosin/metabolism
12.
Chemosphere ; 233: 615-624, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31195265

ABSTRACT

Tylosin (Tyl) is a veterinary antibiotic commonly used in swine and poultry production. Due to metabolic inefficiencies, it enters the environment through manure applications. Ion exchange is an important retention mechanism for Tyl, particularly for smectite clay. The objectives of this study are to characterize the exchange interactions of Tyl with common soil cations in subsoil horizons that contain smectite and to investigate the interactions using in situ Fourier transform infrared (FTIR) spectroscopy. Adsorbed Tyl in pH neutral, smectitic subsoil horizons is divided into exchangeable and nonexchangeable forms. The percentage of adsorbed Tyl that is exchangeable varies from 36% to 43% when Na+ is the competing cation, and from 57% to 66% when Ca2+ competes. In NaX-TylX binary exchange systems, neither Na+ nor Tyl+ is preferred by the clay exchange phase, and the Vanselow selectivity coefficients (KV) for the NaX→TylX exchange reaction range between 0.79 and 1.41. In the CaX2-TylX systems, Tyl+ is preferred by the clay exchange phase when the equivalent fraction of TylX (ETylX) is less than 0.4. The KV values for the CaX2→TylX exchange reaction are at a maximum at the lowest ETylX values, with 17.6

Subject(s)
Soil Pollutants/chemistry , Tylosin/chemistry , Adsorption , Animals , Anti-Bacterial Agents/chemistry , Cations , Clay , Hydrogen-Ion Concentration , Ion Exchange , Manure , Silicates , Soil/chemistry , Soil Pollutants/analysis , Swine
13.
Bioorg Med Chem ; 27(15): 3237-3247, 2019 08 01.
Article in English | MEDLINE | ID: mdl-31229422

ABSTRACT

Bacterial resistance to the existing drugs requires constant development of new antibiotics. Developing compounds active against gram-negative bacteria thereby is one of the more challenging tasks. Among the many approaches to develop successful antibacterials, medicinal chemistry driven evolution of existing successful antibiotics is considered to be the most effective one. Towards this end, the C-20 aldehyde moiety of desmycosin was modified into α-acylamino and α-acyloxy amide functionalities using isonitrile-based Ugi and Passerini reactions, aiming for enhanced antibacterial and physicochemical properties. The desired compounds were obtained in 45-93% yield under mild conditions. The antibacterial activity of the resulting conjugates was tested against gram-negative Aliivibrio fischeri. The antibiotic strength is mostly governed by the amine component introduced. Thus, methylamine derived desmycosin bis-amide 4 displayed an enhanced inhibition rate vs. desmycosin (99% vs. 83% at 1 µM). Derivatives with long acyclic or bulky amine and isocyanide Ugi components reduced potency, whereas carboxylic acid reagents with longer chain length afforded increased bioactivity. In Passerini 3-component products, the butyric ester amide 22 displayed a higher activity (90% at 1 µM) than the parent compound desmycosin (2).


Subject(s)
Aliivibrio fischeri/drug effects , Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Tylosin/analogs & derivatives , Amides/chemical synthesis , Amides/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Tylosin/chemical synthesis , Tylosin/chemistry , Tylosin/pharmacology
14.
Environ Pollut ; 248: 1079-1087, 2019 May.
Article in English | MEDLINE | ID: mdl-31091640

ABSTRACT

This work present aims to evaluate the effect of a conventional wastewater treatment process on the number of nanoparticles, and the role of nanoparticles as a carrier of antibiotics. A set of methods based on asymmetrical flow field flow fractionation coupled with multi-angle light scattering to separate and quantify nanoparticles in real wastewater was established. The characterization of nanoparticles was conducted by transmission electron microscopy, energy dispersive spectrometer, UV-visible spectrophotometer and three-dimensional excitation-emission matrix fluorescence spectroscopy. The adsorption of different sizes of nanoparticles separated from the real wastewater for four targeted antibiotics (sulfadiazine, ofloxacin, tylosin and tetracycline) was studied. The results show that the number of nanoparticles were increased in the wastewater treatment process and the size range between 60 and 80 nm was predominant in wastewater samples. The nanoparticles were mainly composed of O, Si, Al and Ca elements and organic components were in the size range of 0-10 nm. Targeted antibiotics were dominantly adsorbed onto nanoparticles with 60-80 nm size range at each stage. The concentrations of tetracycline adsorbed on nanoparticles were surprisingly increased in the end of the treatment process, while ofloxacin and tylosin had the completely opposite phenomenon to tetracycline. The pH and ionic strength definitely affected the aggregation of nanoparticles and interaction with the antibiotics. It is of great significance to give insights into nanoparticle-antibiotic assemblages for the effective treatment and avoiding the water risks due to nanoparticles' ubiquitous and their risks of carrying antibiotics.


Subject(s)
Anti-Bacterial Agents/analysis , Anti-Bacterial Agents/chemistry , Nanoparticles/chemistry , Ofloxacin/analysis , Sulfadiazine/analysis , Tetracycline/analysis , Tylosin/analysis , Wastewater/chemistry , Water Purification/methods , Adsorption , Fractionation, Field Flow , Microscopy, Electron, Transmission , Ofloxacin/chemistry , Osmolar Concentration , Spectrometry, X-Ray Emission , Spectrum Analysis , Sulfadiazine/chemistry , Tetracycline/chemistry , Tylosin/chemistry , Water/chemistry
15.
Sci Transl Med ; 11(483)2019 03 13.
Article in English | MEDLINE | ID: mdl-30867321

ABSTRACT

There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against Wolbachia This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Two analogs, A-1535469 and A-1574083, were selected. Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis (Brugia malayi and Litomosoides sigmodontis) and onchocerciasis (Onchocerca ochengi). A 1- or 2-week course of oral A-1535469 or A-1574083 provided >90% Wolbachia depletion from nematodes in infected animals, resulting in a block in embryogenesis and depletion of microfilarial worm loads. The two analogs delivered comparative or superior efficacy compared to a 3- to 4-week course of doxycycline or minocycline. A-1574083 (now called ABBV-4083) was selected for further preclinical testing. Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti-Wolbachia macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis.


Subject(s)
Elephantiasis, Filarial/drug therapy , Elephantiasis, Filarial/microbiology , Macrolides/administration & dosage , Macrolides/therapeutic use , Onchocerciasis/drug therapy , Onchocerciasis/microbiology , Wolbachia/physiology , Administration, Oral , Animals , Disease Models, Animal , Elephantiasis, Filarial/blood , Female , Macrolides/adverse effects , Male , Mice, Inbred BALB C , Mice, SCID , Onchocerciasis/blood , Treatment Outcome , Tylosin/blood , Tylosin/chemical synthesis , Tylosin/chemistry , Tylosin/therapeutic use
16.
J Pharm Biomed Anal ; 165: 147-154, 2019 Feb 20.
Article in English | MEDLINE | ID: mdl-30544049

ABSTRACT

In this study, an improved liquid chromatographic (LC) method for the analysis of tylosin and its impurities has been developed. A Kinetex EVO C18 column (150 × 4.6 mm, 2.6 µm) packed with superficially porous particles was used as stationary phase. Gradient elution was applied with two mobile phases (A and B) containing acetonitrile, water and 0.2 M ammonium acetate at different ratios (20:10:70 (v/v/v) for A and 60:10:30 (v/v/v) for B). This volatile mobile phase enables the method to be coupled with mass spectrometry (MS) for additional detection and characterization of tylosin impurities. Selectivity, sensitivity, linear calibration, accuracy, precision and robustness of this analytical method were assessed through method validation. In addition, impurities above 0.05% were characterized via LC-MS/MS. It is the first time that a MS compatible method for analysis of tylosin and its impurities is presented. Moreover, it shows a considerably shorter analysis time than previously published methods.


Subject(s)
Anti-Bacterial Agents/analysis , Chromatography, Liquid/methods , Tandem Mass Spectrometry/methods , Tylosin/analysis , Anti-Bacterial Agents/chemistry , Calibration , Drug Contamination , Porosity , Reproducibility of Results , Sensitivity and Specificity , Tylosin/chemistry
17.
Daru ; 26(2): 155-164, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30361888

ABSTRACT

BACKGROUND: The aim of our research work was to investigate the relative potencies of matrix components of tylosin, a multi-component antibiotic, and establishing a quantitative relationship between content and potency of each component. METHODS: The potencies of tylosin matrix components were determined by using three bioassay methods. The content of tylosin components (tylosin A, B, C, and D) in different tylosin samples were determined by using high pressure liquid chromatography (HPLC) technique and their theoretical potencies were calculated. Equivalency of theoretical and microbiological potencies for each sample was evaluated using statistical analysis. RESULTS: The highest amount of tylosin B content was found in tylosin phosphate and tartrate (up to 19%). Tylosin D content in all tylosin samples varied in the range of 0.03 to 18.73%. Tylosin A, B, and C showed similar sensitivity to the Kocuria rhizophila, the test organism in agar-diffusion method, while the potency of tylosin D was 39% of A. In the turbidimetric methods by Staphylococcus aureus, tylosin D and B responses to A component were ranged from 22.5 to 22.8% and 77.3 to 79.3%, respectively, while potencies of tylosin C and A were almost equal. The biopotency conversion factors were not resulted to a single factor, due to the different antibacterial activity of tylosin components. CONCLUSION: Our findings indicated that defining individual limit for the low active matrix components and for the total of other components with similar high activity could improve the accuracy of potency results. Graphical abstract ᅟ.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Tylosin/chemistry , Tylosin/pharmacology , Chromatography, High Pressure Liquid , Microbial Sensitivity Tests , Micrococcaceae/drug effects , Nephelometry and Turbidimetry , Staphylococcus aureus/drug effects , Tartrates/analysis
18.
Molecules ; 23(8)2018 Jul 31.
Article in English | MEDLINE | ID: mdl-30065238

ABSTRACT

Tilmicosin is a widely used antibiotic in veterinary applications. Its antimicrobial activity is ranged from Gram-positive and some Gram-negative bacteria towards activities against Mycoplasma and Chlamydia. Adsorption affinity of tilmicosin antibiotics towards bovine serum albumin was investigated by both spectroscopic (UV-vis, Photoluminescence) and calorimetric methods. The interaction was determined on the basis of quenching of albumin by tilmicosin. Results confirm noncovalent binding of tilmicosin on bovine serum albumin with 1:1 stoichiometry associated with pK = 4.5, highlighting possible removal of tilmicosin molecules from the albumin surface through exchange reactions by known competitor molecules. Calorimetric measurements have confirmed the weak interaction between tilmicosin and albumin and reflect enhanced denaturation of the albumin in the presence of tilmicosin antibiotic. This process is associated with the decreased activation energy of conformational transition of the albumin. It opens a new, very quick reaction pathway without any significant effect on the product by noncovalent binding the tilmicosin molecules to the protein molecules. Results highlight the medical importance of these investigations by considerable docking of the selected antibiotic molecules on serum albumins. Although the binding may cause toxic effects in living bodies, the strength of the binding is weak enough to find competitor molecules for effective removals from their surface.


Subject(s)
Anti-Bacterial Agents/chemistry , Serum Albumin, Bovine/chemistry , Serum Albumin/chemistry , Tylosin/analogs & derivatives , Veterinary Drugs/chemistry , Animals , Calorimetry , Cattle , Goats , Kinetics , Protein Binding , Sheep , Spectrometry, Fluorescence , Swine , Thermodynamics , Tylosin/chemistry
19.
Article in English | MEDLINE | ID: mdl-30016205

ABSTRACT

Mycotoxin binders are feed additives which are mixed in the feed to adsorb mycotoxins and thereby reducing their toxic effects on animals. Interactions with orally administered veterinary medicinal products, such as antimicrobials or coccidiostats, have been reported previously. This paper describes an in vitro model to screen the interaction between mycotoxin binders and veterinary drugs with respect to the non-specific binding of drugs. It is designed as a static setup using a single concentration of drug and binder in a feed-containing or a feed-plus-mycotoxin-containing matrix, buffered at different pH values. The model was applied to two frequently used antimicrobials in veterinary medicine, doxycycline (DOX) and tylosin (TYL), one major mycotoxin, aflatoxin B1 (AFB1), and four mycotoxin binders. Proportions of feed, DOX or TYL, AFB1, and binder are equivalent to the in vivo situation for broiler chickens, while pH and volume of the buffer are representative of the gastrointestinal tract of chickens. A substantial binding of DOX (~ 88%) and TYL (~ 66%) to the feed-matrix was observed. For the mycotoxin binders, similar results were obtained for DOX and TYL; more specifically up to an inclusion rate of 20 g binder/kg feed, no significant binding was demonstrated, determined as the free concentration of DOX and TYL. A single exception was noticed for TYL and one specific bentonite-based mycotoxin binder, for which no significant interaction could be demonstrated up to 10 g binder/kg but there was an effect at 20 g/kg. In all cases, there was no competition between the tested drugs DOX or TYL and the mycotoxin AFB1 for binding to the bentonite-based mycotoxin binder.


Subject(s)
Aflatoxin B1/chemistry , Animal Feed/analysis , Bentonite/chemistry , Models, Chemical , Veterinary Drugs/chemistry , Administration, Oral , Adsorption , Animals , Buffers , Chickens , Doxycycline/administration & dosage , Doxycycline/chemistry , Food Addiction , Tylosin/administration & dosage , Tylosin/chemistry , Veterinary Drugs/administration & dosage
20.
Chemosphere ; 193: 912-920, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29874766

ABSTRACT

Tylosin, an antibiotic used for maintaining livestock health, is a macrolide structurally similar to a number of important, often prescribed human antibiotics. Because of this relationship, tylosin presents a potential threat of antimicrobial resistance from environmental buildup. This work investigated tylosin sorption to natural diatomaceous earth product (DE) and the types of physical interactions responsible for sorption. Most sorption processes were best described by the Langmuir model when compared with Freundlich model. Heat of sorption (ΔH) was 1.14 kJ mol-1 indicating a physisorption process. Change in entropy (ΔS) was 119 J mol-1. Sorption was evaluated from aqueous solution with various H+, KCl and Urea concentrations. In 0.01 M phosphate buffer (PB) pH 6.6, a maximum sorption capacity of 15 mg tylosin per g of DE was achieved. Changing the pH to 2.9 or 11.2 resulted in decreased sorption of tylosin (13 and 10 mg g-1, respectively). Addition of 1 M KCl to 0.01 M PB pH 6.6 decreased sorption of tylosin to DE with the maximum binding capacity of 7 mg g-1. Sorption in 1.0 M urea, 0.01 M phosphate buffer pH 6.6 showed a maximum sorption of 13 mg g-1. Based on these results, the sorption of tylosin appears to be a physisorption process, with charge-charge interactions being the mode of sorption at neutral pH and small contributions from secondary interactions. This information will be useful for developing effective strategies for mitigating tylosin and other antimicrobial's impact on the environment.


Subject(s)
Biophysical Phenomena , Diatomaceous Earth/chemistry , Tylosin/chemistry , Adsorption , Kinetics
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