The tylosin-biosynthetic (tyl) gene cluster of Streptomyces fradiae contains ancillary genes that encode functions normally associated with primary metabolism. These can be disrupted without loss of viability, since equivalent genes (presumably used for 'housekeeping' purposes) are also present elsewhere in the genome. The tyl cluster also contains two genes that encode products unlike any proteins in the databases. Two ancillary genes, metF (encoding N5,N10-methylenetetrahydrofolate reductase) and metK, encoding S-adenosylmethionine synthase, flank one of the 'unknown' genes (orf9) in the tyl cluster. In a strain of S. fradiae in which all three of these genes were disrupted, tylosin production was reduced, although this effect was obscured in media supplemented with glycine betaine which can donate methyl groups to the tetrahydrofolate pool. Apparently, one consequence of the recruitment of ancillary genes into the tyl cluster is enhanced capacity for transmethylation during secondary metabolism.
来源:Hazardous Substances Data Bank (HSDB)
代谢
关于致病性诺卡氏菌对大环内酯类抗生素（沙链霉素和泰乐菌素）的敏感性研究显示，大多数被检测的诺卡氏菌种类对这两种抗生素都有很高的耐药性，尽管N. nova（诺卡氏菌属的一个种）对此有一定的敏感性。N. asteroides IFM 0339（一种诺卡氏菌）通过在2'-OH位的糖基化或糖基化并还原20位的甲酰基团，将这些大环内酯类抗生素转化为无活性的代谢物。通过核磁共振（NMR）和质谱（MS）数据确定了代谢物的结构，分别为2'-[O-(beta-D-吡喃葡萄糖基)]沙链霉素（2），2'-[O-(beta-D-吡喃葡萄糖基)]泰乐菌素（5）和20-二氢-2'-[O-(beta-D-吡喃葡萄糖基)]泰乐菌素（4）。
Studies on the susceptibility of pathogenic Nocardia to macrolide antibiotics, chalcomycin and tylosin, showed that most of the Nocardia species examined were highly resistant to both antibiotics, although N. nova was moderately susceptible. N. asteroides IFM 0339 converted these macrolides into inactive metabolites by glycosylation at 2'-OH or glycosylation and reduction of the 20-formyl group. The structures of the metabolites were determined from NMR and MS data to be 2'-[O-(beta-D-glucopyranosyl)]chalcomycin (2), 2'-[O-(beta-D-glucopyranosyl)]tylosin (5) and 20-dihydro-2'-[O-(beta-D-glucopyranosyl)]tylosin (4).
Tylosin is produced by Streptomyces fradiae via a combination of polyketide metabolism and synthesis of three deoxyhexose sugars, of which mycaminose is the first to be added to the polyketide aglycone, tylactone (protylonolide). Previously, disruption of the gene (tylMII) encoding attachment of mycaminose to the aglycone unexpectedly abolished accumulation of the latter, raising the possibility of a link between polyketide metabolism and deoxyhexose biosynthesis in S. fradiae. However, at that time, it was not possible to eliminate an alternative explanation, namely, that downstream effects on the expression of other genes, not involved in mycaminose metabolism, might have contributed to this phenomenon. Here, it is shown that disruption of any of the four genes (tylMI--III and tylB) specifically involved in mycaminose biosynthesis elicits a similar response, confirming that production of mycaminosyl-tylactone directly influences polyketide metabolism in S. fradiae. Under similar conditions, when mycaminose biosynthesis was specifically blocked by gene disruption, accumulation of tylactone could be restored by exogenous addition of glycosylated tylosin precursors. Moreover, certain other macrolides, not of the tylosin pathway, were also found to elicit qualitatively similar effects. Comparison of the structures of stimulatory macrolides will facilitate studies of the stimulatory mechanism.
Three glycosyltransferases are involved in tylosin biosynthesis in Streptomyces fradiae. The first sugar to be added to the polyketide aglycone (tylactone) is mycaminose and the gene encoding mycaminosyltransferase is orf2* (tylM2). However, targeted disruption of orf2* did not lead to the accumulation of tylactone under conditions that normally favor tylosin production; instead, the synthesis of tylactone was virtually abolished. This may, in part, have resulted from a polar effect on the expression of genes downstream of orf2*, particularly orf4* (ccr) which encodes crotonyl-CoA reductase, an enzyme that supplies 4-carbon extender units for polyketide metabolism. However, that cannot be the entire explanation, since tylosin production was restored at about 10% of the wild-type level when orf2* was re-introduced into the disrupted strain. When glycosylated precursors of tylosin were fed to the disrupted strain, they were converted to tylosin, confirming that two of the three glycosyltransferase activities associated with tylosin biosynthesis were still intact. Interestingly, however, tylactone also accumulated under such conditions and, to a much lesser extent, when tylosin was added to similar fermentations. It is concluded that glycosylated macrolides exert a pronounced positive effect on polyketide metabolism in S. fradiae.
IDENTIFICATION AND USE: Tylosin is used as an aid in the treatment of chronic respiratory disease associated with Mycoplasma gallisepticum in chickens. It is also used for the reduction in severity of effects of infectious sinusitis associated with Mycoplasma gallisepticum in turkeys. In honey bees, it is used for the control of American Foulbrood (Paenibacillus larvae). Finally, tylosin is used for the treatment and control of swine dysentery associated with Brachyspira hyodysenteriae. HUMAN EXPOSURE AND TOXICITY: Contact dermatitis caused by tylosin has been reported by farm workers and individuals employed in veterinary medicine. ANIMAL STUDIES: Tylosin was placed in one eye of rabbits in an amount of 0.1 mL, 52 mg or 58 mg of Tylan 200 Injection, Tylosin Concentrate or Tylan Soluble, respectively. Tylan 200 Injection caused very slight conjunctival hyperemia, which cleared within 48 hr. Tylosin Concentrate caused corneal dullness, slight corneal opacity, slight to moderate iritis and moderate conjunctivitis within 1 hr post-exposure. However, all irritation cleared within 14 days. Tylan Soluble caused slight to moderate corneal opacity, marked iritis and moderate conjunctivitis within 1 hr. In this study, all irritation cleared within 7 days post exposure. Female rats were treated subcutaneously with tylosin up to 100 mg/kg bw per day for 28 days without any toxicological effects. Male and female rats were administered tylosin base in the diet for 1 year at levels of 0, 1000, 5000 and 10,000 mg/kg. Treated rats appeared moderately hyperirritable and hyperactive from 7 to 12 months on test, but there was no mortality attributable to treatment. Increased numbers of lymphocytes, decreased numbers of neutrophils and increased urine pH were observed in females given 5000 and 10,000 mg/kg diet. Microscopic examination revealed a slight increase in pituitary tumors in females of all treated groups: 1, 3, 4 and 3 adenomas and 0, 0, 1 and 0 carcinomas at 0, 1000, 5000 and 10,000 mg/kg diet, respectively. In another rat study, male and female rats were fed diets containing 0, 20,000, 50,000, 100,000 or 200,000 mg tylosin base/kg diet for 2 years. Body weight gain and food intake were reduced at the two highest doses. All high-dose rats died within 12 months and exhibited high incidences of malnutrition and atrophy/necrosis of lymphoid organs. In a 2-year study, dogs and mixed-breed dogs were given oral doses of 0, 1, 10 or 100 mg tylosin base/kg bw per day by capsule. After this study had progressed for 153 days, it was expanded by adding further groups of male and female mongrel dogs given doses of 200 or 400 mg tylosin base/kg bw per day for the remainder of the study period. Occasional diarrhea and vomiting occurred in dogs given 10-400 mg/kg bw per day. Transient elevated bromosulfophthalein retention times were recorded in two dogs at 100 mg/kg bw per day and one dog at 400 mg/kg bw per day. At necropsy, mild pyelonephritis was found in one dog given 200 mg/kg bw per day, and bilateral nephrosis, mild chronic pyelonephritis and mild chronic cystitis were seen in one dog given 400 mg/kg bw per day. Tylosin base was given by gavage to mice at doses of 0, 100, 500 or 1000 mg/kg bw per day on gestation days 7-12. Four mice per group given 0 or 500 mg/kg bw per day were allowed to deliver, the remainder were killed on gestation day 18. There were no treatment-related differences in maternal body weight gains or development of fetuses. No adverse effects were noted in delivered offspring at 7 and 9 weeks. Female rats were given diets containing 0, 1000, 10,000 or 100,000 mg tylosin base/kg, dosed on gestation days 0-20 and killed on gestation day 20. At 100,000 mg/kg diet, body weight was depressed in dams and fetuses, and ossification was retarded. Some females from the control and the two highest dose groups were treated from gestation day 0 to postnatal day 21 and allowed to deliver. The body weight gain of offspring was lower at 100,000 mg/kg diet. Tylosin tested positive in an in vitro assay for the induction of gene mutations in mouse lymphoma cells but tested negative in an in vitro assay for the induction of gene mutations in HGPRT+ Chinese hamster ovary cells, an in vitro chromosomal damage assay in Chinese hamster ovary cells and an in vivo assay for cytogenetic damage in mouse bone marrow. ECOTOXICITY STUDIES: Tylosin was toxic in the freshwater green alga investigated over 72-hr exposures.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
皮肤致敏剂 - 一种可以诱导皮肤产生过敏反应的制剂。
Skin Sensitizer - An agent that can induce an allergic reaction in the skin.
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
The interaction between bentonite and tylosin was investigated in broiler chickens, based on pharmacokinetic characteristics obtained in vivo. Simultaneous oral administration of bentonite and tylosin significantly lowered plasma levels of tylosin and reduced the area under the plasma concentration-time curve (AUC(0-inf)), maximal plasma concentration (C(max)), time to maximal plasma concentration (T(max)) and relative oral bioavailability. The results prove unambiguously the binding of tylosin by bentonite. Simultaneous administration of tylosin (in the drinking water or feed) and bentonite (mixed in the feed as a mycotoxin binder) should therefore be avoided.
In humans, clinically relevant drug-drug interactions occur with some macrolide antibiotics via the formation of stable metabolic intermediate (MI) complexes with enzymes of the cytochrome P4503A (CYP3A) subfamily. The formation of such complexes can result in a decreased biotransformation rate of simultaneously administered drugs. In previous studies it was shown that the veterinary antibiotic tiamulin was also able to form a stable MI complex in pigs and rats. In the present study the relative CYP3A inhibiting potency and MI complex formation of a series of macrolide antibiotics and tiamulin were studied in microsomal fractions of goat and cattle and in a cell-line expressing bovine CYP3A. Tiamulin and triacetyloleandomycin (TAO) were found to be effective inhibitors of CYP450 activity in all systems tested. Erythromycin and tilmicosin were found to be relatively less effective inhibitors of CYP450 activity in microsomes, and their activity in the bovine CYP3A4 expressing cell line was relatively weak. Tylosin was shown to be a weak inhibitor in microsomes and not in the cell line, whereas spiramycin had no effect at all. MI-complex formation measured by spectral analysis was seen with TAO, tiamulin, erythromycin and tylosin, but not with tilmicosin and spiramycin. Although additional factors play a role in vivo, these results may explain potential drug-drug interactions and differences between related compounds in this respect.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
The pharmacokinetics and oral bioavailability of tylosin tartrate and tylosin phosphate were carried out in broiler chickens according to a principle of single dose, random, parallel design. The two formulations of tylosin were given orally and intravenously at a dose level of 10 mg/kg b.w to chicken after an overnight fasting (n = 10 chickens/group). Serial blood samples were collected at different time points up to 24 hr postdrug administration. A high performance liquid chromatography method was used for the determination of tylosin concentrations in chicken plasma. The tylosin plasma concentration's time plot of each chicken was analyzed by the 3P97 software. The pharmacokinetics of tylosin was best described by a one-compartmental open model 1st absorption after oral administration. After intravenous administration the pharmacokinetics of tylosin was best described by a two-compartmental open model, and there were no significant differences between tylosin tartrate and tylosin phosphate. After oral administration, there were significant differences in the Cmax (0.18 + or - 0.01, 0.44 + or - 0.09) and AUC (0.82 + or - 0.05, 1.57 + or - 0.25) between tylosin phosphate and tylosin tartrate. The calculated oral bioavailability (F) of tylosin tartrate and tylosin phosphate were 25.78% and 13.73%, respectively. Above all, we can reasonably conclude that, the absorption of tylosin tartrate is better than tylosin phosphate after oral administration.
/MILK/ The aim of this study is to determine the pharmacokinetics of tylosin and tilmicosin in serum and milk in healthy Holstein breed cows (n = 12) and reevaluate the amount of residue in milk. Following the intramuscular administration of tylosin, the maximum concentrations (C max) in serum and milk were found to be 1.30 + or - 0.24 and 4.55 + or - 0.23 ug/mL, the time required to reach the peak concentration (t max) was found to be 2nd and 4th hour, and elimination half-live were found to be 20.46 + or - 2.08 and 26.36 + or - 5.55 hour, respectively. Following the subcutaneous administration of tilmicosin, the C max in serum and milk were found to be 0.86 + or - 0.20 and 20.16 + or - 1.13 ug/mL, the t max was found to be 1st and 8th hr, and the elimination half life were found to be 29.94 + or - 6.65 and 43.02 + or - 5.18 hr, respectively. AUCmilk/AUCserum and C max-milk/C max-serum rates, which are indicators for determining the rate of drugs that pass into milk, were, respectively, calculated as 5.01 + or - 0.72 and 3.61 + or - 0.69 for tylosin and 23.91 + or - 6.38 and 20.16 + or - 1.13 for tilmicosin. In conclusion, it may be stated that milk concentration of tylosin after parenteral administration is higher than expected like tilmicosin and needs more withdrawal period for milk than reported.
Biological availability and pharmacokinetic properties of tylosin were determined in broiler chickens after oral and iv administration at a dose of 10 mg/kg. The calculated bioavailability--F%, by comparing AUC values--oral and AUC--iv, ranged from 30%-34%. After intravenous injection tylosin was rapidly distributed in the organism, showing elimination half-life values of 0.52 hr and distribution volume (Vd) of 0.69 L/kg, at a clearance rate (Cl) of 5.30 +/- 0.59 mL/min/kg. After oral administration, tylosin has a similar distribution volume (Vd = 0.85 L/kg), while the elimination half-life of 2.07 hr was four times bigger than after iv administration at Cl = 4.40 +/- 0.27 mL/min/kg. The obtained value tmax = 1.5 hr for tylosin after oral administration indicates that using this antibiotic with drinking water in broiler chickens is the method of choice. However, a relatively low value Cmax = 1.2 micrograms/ml after oral administration of tylosin shows that dosing of this antibiotic in broiler chickens should be higher than in other food producing animals.
/MILK/ Antibiotic residues in milk above tolerance levels interfere with dairy product processing and pose potential health risks to consumers. Residue avoidance programmes include, among other components, the observance of withdrawal times indicated in label instructions. Persistence of antibiotics in milk following treatment is influenced by drug, dosage, route of administration, body weight and mammary gland health status. Compositional changes that take place during intramammary infection (IMI) can affect antibiotic excretion in milk, thus modifying milk withdrawal time. The objectives of this study were to validate sensitivity and specificity of a qualitative microbiological method (Charm AIM-96) to detect tylosin in bovine composite milk and to determine the influence of subclinical IMI in tylosin excretion following intramuscular administration. For test validation, two groups of approximately 120 cows were used; one received a single intramuscular injection of tylosin tartrate at a dose of 20 mg/kg, while the other group remained as untreated control. Test sensitivity and specificity were 100% and 94.1% respectively. To determine the influence of subclinical IMI in tylosin excretion, two groups of seven cows, one with somatic cell counts (SCC) < or =250 000 cells/ml and the other with SCC > or =900 000, were administered a single intramuscular injection of tylosin tartrate at a dose of 20 mg/kg. Milk samples were obtained every 12 h for 10 days following treatment. Milk tylosin excretion averaged between 5 and 9 days for cows with low and high SCC respectively (P < 0.0001). Compositional changes in cows with high SCC most likely affect the pharmacokinetic characteristics of tylosin, extending the presence of the antibiotic in milk, thus influencing milk withdrawal times.
ANTHELMINTIC COMPOUNDS AND COMPOSITIONS AND METHOD OF USING THEREOF
申请人：Meng Charles Q.
公开号：US20140142114A1
公开（公告）日：2014-05-22
The present invention relates to novel anthelmintic compounds of formula (I) below:
wherein
Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X
1
, X
2
, X
3
, X
4
, X
5
, X
6
, X
7
and X
8
are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.
The present invention provides cyclic depsipeptide compounds of formula (I) wherein the stereochemical configuration of at least one carbon atom bearing the groups Cy1, Cy2, R1, R2, R3, R4, Ra and Rb is inverted compared with the naturally occurring cyclic depsipeptide PF1022A. The invention also provides compositions comprising the compounds that are effective against parasites that harm animals. The compounds and compositions may be used for combating parasites in or on mammals and birds. The invention also provides for an improved method for eradicating, controlling and preventing parasite infestation in birds and mammals.
Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): or a stereoisomer, tautomer or salt thereof, wherein R1, R2, R3, R4, R5, L, L1, L2, M and n are as defined herein. Methods associated with preparation and use of such compounds are also provided.
[EN] COMPOUNDS USEFUL FOR TREATING A MANNHEIMIA HAEMOLYTICA OR HISTOPHILUS SOMNI INFECTION<br/>[FR] COMPOSÉS UTILES POUR TRAITER UNE INFECTION PAR MANNHEIMIA HAEMOLYTICA OU HISTOPHILUS SOMNI
申请人：INTERVET INT BV
公开号：WO2018115421A1
公开（公告）日：2018-06-28
The present invention discloses compounds of formula (I) that are useful in the treatment of respiratory diseases of animals, especially Bovine or Swine Respiratory disease (BRD and SRD).
Compounds that are Analogs of Squalamine, Used as Antibacterial Agents
申请人：VIRBAC
公开号：US20180042942A1
公开（公告）日：2018-02-15
The invention relates to compounds of formula (I), to the pharmaceutical compositions comprising same, and to the use thereof in the treatment of bacterial, fungal, viral and parasitic infections or in the treatment of cancer in humans or animals. In formula (I), R1 and R2 are as defined in claim
1.
