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 a