Streptomycins

Streptomycin when applied in a concentration range between 30 and 240 pg mL controlled fire blight and caused no phytotoxic effects on leaves and no fruit rus-setting [54, 55], and the antibiotic has been used in USA since 1955. In numerous orchard trials in the 1950s and 1960s the efficiency of streptomycin treatments for control of fire blight was determined. Because of its limited systemic activity, spray treatments should completely cover all possible infection sites, such as open flowers, shoots and leaves. For fire blight control streptomycin is also used in New Zealand, some European countries and Middle Eastern countries [49]. 

Streptomycin is also permitted in USA on tobacco for control of wild fire (P. syringae pv. tabad) and blue mold (Peronospora tabacina), which is the only fungal pathogen controlled by streptomycin [57]. 

Highly resistant strains of M. tuberctdosis developed under in vitro conditions shortly after application of streptomydn to control tuberculosis [61]. Streptomycin-resistant strains of E. amylovora were first deteded in 1971 in pear orchards of California [62, 63]. Subsequently, streptomydn-resistant E. amylovora-strains were reported from areas where the antibiotic has been applied intensively for fire blight control, such as in several western states of the USA [64-66] and outside the USA, e.g., in Egypt [67] and in New Zealand [68]. 

The emergence of streptomycin-resistant strains in pear orchards in California in 1971 and in Michigan in 1990 has stimulated studies on emergence, development and mechanisms of streptomycin resistance in E. amylovora. Mechanisms of resistance to streptomydn indude alterations of the ribosomal target site, production of streptomycin-modifying enzymes and reduced uptake and thus access to the target site [69, 70], 

Two phenotypes, highly resistant [minimal inhibitory concentration (MIC) of 2000 xg mL j and moderately resistant strains (MIC 500 to 750 pg mL ) to streptomycin have been detected in the E. amylovora populations [64, 71, 72]. Spontaneous mutants with high level of resistance to streptomycin were isolated at a frequency of 4 of 10 bacteria and mutants with moderate resistance level were obtained at a frequency of 0.1 of 10 bacteria. 

Streptomycin is a strong sensitizer and obsolete in topical therapy, but still presents an occupational hazard to nurses and veterinarians, because of leakage from syringes. 

Xanthocillin has been used in leg ulcer treatment and has caused several cases of contact allergy (Heijer 1961). 

Mafenide (sulfamylon), as hydrochloride and acetate is extensively used in treatment of bums, and has significantly lowered the mortality from bum wound sepsis (YAFEE and Dressler 1969). It was found to be a common sensitizer in studies performed in Munich, outnumbered only by benzocaine in the years from 1960 to 1965 (Bandmann 1966). Mafenide acetate must not be used in patch testing, because patients sensitized to mafenide hydrochloride do not react to mafenide acetate (ScHREUS 1950). Cross-reactions to other related esters ofp-aminobenzoic acid occur relatively often (Bandmann 1967 Schulz 1962). Sulfonamides do not cross react with mafenide. Bandmann and Breit (1973) have reviewed the mafenide story. 

Although the position of the linkage between the streptose and streptidine units has not been completely settled, the most probable structure of streptomycin is given in the accompanying formula (XIX) 79, 80, 82,83). 

For a review of the subject and detailed references see R. U. Lemieux and M. L. Wolfrom, Advances in Carbohydrate Chem. 3, 337 (1947). 

Several derivatives of streptomycin have been prepared 86). These have 

The fatty acid components are usually lignoceric acid, CH3(CH2)22— COOH (of kerasin), 2-hydroxylignoceric acid (of phrenosin), A -lignoceric acid (of nervone), behenic acid, or stearic acid. 

Sphingosine has been shown to be 2-amino-l,3-dihydroxy-4- rans-D-er /iro-octadecene (89). 

The above sterilized medium was inoculated with 11 liters of seed inoculum having a bacterial count of approximately 20 billion per cc. The tank was fermented at 37°C without pH adjustment, aeration, or other modification for 14 hours at the end of which time 320 cc of 50% dextrose was added. After this the pH was adjusted to 7.0 at 15 minute intervals with 5.0 N sodium hydroxide. The volume of sodium hydroxide required for neutralization was noted and 115% of this volume of 50% dextrose solution added after each pH adjustment. At the end of about 8 hours the bacterial count had ceased to increase and the fermentation was terminated. At this time the fermentation medium contained approximately 1,000 units of streptokinase per cc. 

Ablondi, F.B. and Adam, J.N. Jr. U.S. Patent 2,701,227 February 1, 1955 assigned to American Cyanamid Company 

Singher, H.O. and Zuckerman, L. U.S. Patent 3,016,337 January 9,1962 assigned to Ortho Pharmaceutical Corporation 

Chemical Name 0-2-deoxy-2-(methylamino)-o -L-glucopyranosyl-(1- 2)-0-5-deoxy-3-C-formyl-a-L-lyxofuranosyl-(1- 4)-N,N -bis(aminoiminomethyl)-D-streptamine 

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Streptomycin B (mannosidostreptomycin) has a mannose molecule attached to the methylglucosamine group, and is the first antibacterial product made, but is enzymatically converted to streptomycin later in the fermentation. 

Dihydrostreptomycin, in which the CHO group in the middle ring is replaced by CH2OH, is made by the catalytic reduction of streptomycin, and has similar antibacterial properties. 

Antibiotics. Solvent extraction is an important step in the recovery of many antibiotics (qv) such as penicillin [1406-05-9] streptomycin [57-92-17, novobiocin [303-81-1J, bacitracin [1405-87-4] erythromycin, and the cephalosporins. A good example is in the manufacture of penicillin (242) by a batchwise fermentation. Amyl acetate [628-63-7] or -butyl acetate [123-86-4] is used as the extraction solvent for the filtered fermentation broth. The penicillin is first extracted into the solvent from the broth at pH 2.0 to 2.5 and the extract treated with a buffet solution (pH 6) to obtain a penicillin-rich solution. Then the pH is again lowered and the penicillin is re-extracted into the solvent to yield a pure concentrated solution. Because penicillin degrades rapidly at low pH, it is necessary to perform the initial extraction as rapidly as possible for this reason centrifugal extractors are generally used. 

Antibiotics. The genes involved in the synthesis of a variety of antibiotics have been isolated (34,35). These include antibiotics such as erythromycin, streptomycin, and also peptide antibiotics such as gramicidin and tyrocidin. Characterization of these gene products facUitates the design of novel antibiotics. In addition, overexpression of some of these gene products is also expected to improve the yield of the antibiotic (34,35). 

Antibiotics approved for use as growth enhancers in Hvestock and poultry include bacitracins, bambermycins, Hncomycin [154-21 -2] penicillin [69-53 ] streptomycin [57-92-1], tetracycHnes, tiamulin [55297-95-5] tylosin [1401-69-0] and virginiamycin [11006-76-1] (61). 

Pharmaceutical. Ion-exchange resins are useful in both the production of pharmaceuticals (qv) and the oral adrninistration of medicine (32). Antibiotics (qv), such as streptomycin [57-92-17, neomycin [1404-04-2] (33), and cephalosporin C [61-24-5] (34), which are produced by fermentation, are recovered, concentrated, and purified by adsorption on ion-exchange resins, or polymeric adsorbents. Impurities are removed from other types of pharmaceutical products in a similar manner. Resins serve as catalysts in the manufacture of intermediate chemicals. 

In 1939 the isolation of a mixture of microbial products named tyrotbricin from a soil bacillus was described. Further investigation showed this material to be a mixture of gramicidin and tyrocidine. In rapid succession the isolation of actinomycin (1940), streptothricin (1942), streptomycin (1943), and neomycin (1949), produced by Streptomjces were reported and in 1942 the word antibiotic was introduced. Chloramphenicol, the first of the so-called broad spectmm antibiotics having a wide range of antimicrobial activity, was discovered in 1947. Aureomycin, the first member of the commercially important tetracycline antibiotics, was discovered in 1948. 

Among the older aminoglycoside derivatives, kanamycin A and sisomicin were, at one time, a significant part of medical practice, but have now been largely replaced by the compounds Hsted in Table 1. Streptomycin is stiH used in a few restricted situations. 

R = R = H) are intermediate, and gentamicin and tobramycin are most susceptible (66). Resistance to streptomycin is widespread, and its use is currently confined primarily to infections caused by Mycobacterium tuberculosis Yersiniapestis and Francisella tularensis. 

Before the discovery of streptomycin, pyrazinamide (126) was one of the front runners in the treatment of tuberculosis. A broad spectrum of biological activity has been associated with pyrazine derivatives, ranging from the herbicidal activity of (127) to antibiotic activity... 

Antibiotics such as penicillin, streptomycin, tetracyclines, chloramphenicol, and antifungals ... 

Substitution of an amino group into the molecule affords an iigent with antibacterial activity. Although seldom used alone, l, ira- aminosalicylic acid (PAS, 7) has been employed as an adjunct Id streptomycin and isoniazid in treatment of tuberculosis. 

Control of tuberculosis, long one of the scourges of mankind, began with the introduction of effective antibacterial agents. Thus, this disease was treated initially with some small measure of success with various sulfa drugs the advent of the antibiotic, streptomycin, provided a major advance in antitubercular therapy, as did the subsequent discovery of isoniazid and its analogs. 

Dihydrostreptomycin sulfate may be prepared from streptomycin sulfate by catalytic hydrogenation (Merck, Pfizer, Cyanamid), electrolytic reduction (Schenley, Olin Mathieson), or by sodium boro hydride reduction (Bristol), or by isolation from a fermentation process (Takeda). 

Calf kidneys, dog kidneys and rhesus monkey kidneys were treated with trypsin to give suspensions of cells. The suspensions were centrifuged and the packed cells diluted with 400 volumes (calf cells) or 200 volumes (dog cells and rhesus monkey cells) of a growth medium consisting of 5% horse serum and 0.5% lactalbumen hydrolysate in Earle s saline, with 100 units/ml each of penicillin and streptomycin. These media were used separately to produce Semliki Forest/calf interferon, Semliki Forest/dog interferon and Semliki Forest/rhesus monkey interferon. The cell-containing growth medium was dispensed into 500 ml medical flat bottles (70 ml in each). The cultures were incubated at 36°C. Confluent sheets of cells (monolayers) were formed in 5 to 6 days. The growth medium was then removed and the monolayers were washed with isotonic phosphate-buffered saline, pH 7.5. 

The alcohol-ether solution is washed with 100 cc of water and the brown aqueous layer is drawn off and added to the first aqueous layer. The aqueous solution is neutralized to pH 6 to 7 with dilute sodium hydroxide and any precipitate that forms is filtered off and discarded. A faintly colored aqueous solution containing streptomycin is thus obtained. 

Streptomycesgriseus No. 3570 Ca ndicldin Streptomyces griseus Streptomycin Streptomyces halstedii Carbomycin... 

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