384 



DESCRIPTIONS OF ANTIBIOTICS 



Streptovariciiis 



Produced by: Streptoniyres spectahilis. 



Synonym: Dalacin. 



Method of extraction: Culture-filtrate extracted 

 with ethyl acetate. Concentrated extract pre- 

 cipitated by addition of 4 vohunes of technical 

 hexane. Precipitate dissolved in methyl chloride 

 and reprecipitated by addition of 5 volumes of 

 hexane. Partially crystalline precipitate washed 

 with hexane and dried in vacuo to give the strep- 

 tovaricin "complex" (2). Components separated 

 by chromatography (agent not stated, toluene- 

 ethylene glycol system) (7), or by countercur- 

 rent distribvition (water-95 per cent ethanol-cyclo- 

 hexane-ethyl acetate, equal parts) (2). 



Chemical and physical properties: "Complex" is 

 said to be made up of 60 per cent antimicrobial 

 substances and 40 per cent inactive material. Par- 

 tially crystalline and bright orange-yellow ma- 

 terial; m.p. 144-147°C (decomposition). Data 

 given for a specific lot of the "complex." Soluble 

 in dimethylformamide and 95 per cent ethanol in 

 excess of 500 mg per ml. Soluble in methanol, bu- 

 tanol, lower ketones, methylene chloride, chloro- 

 form, and the lower acetates. Slightly soluble in 

 water (0.7 mg per ml). Nearly insoluble in hexane, 

 ether, carbon tetrachloride, and benzene. Specific 

 absorbance of 7.7 at 435 m,u (visible light) is de- 

 stroyed in alkaline but not acidic solution; ultra- 

 violet absorption maximum at 244.5 m/.t, with a 

 shoulder at 263 m^ and a plateau at 316 m/u.. [a]'^ = 

 +288° (c = 0.31 per cent in absolute ethanol). 

 Infrared spectrum given iii reference 2. Indicator 

 properties: yellow at acid pH; red-amber at alka- 

 line pH. Positive FeCls and iodoform tests. Nega- 

 tive Benedict, ninhydrin, Alolisch, Zimmerman, 

 and Liebermann tests. Labile to alkali; practically 

 all activity irreversibly lost in 3 da,ys at pH 7.8. 

 Complex and Components A, B, and C quite un- 

 stable in distilled water, pH 6.8 buffer, or organic 

 culture medium at 37°C, losing 85 to 90 per cent 

 of activity in 40 hours. Components A to E are 

 bright orange substances having the following Rf 

 values on paper chromatography; 0.13, 0.37, 0.77, 

 and 0.88; the last two do not separate in this sj's- 

 tem (cyclohexane-chloroform-water, 1:8:2) (1, 2, 

 5, 7, 9). 



Biological activity: Complex: Active on gram- 

 positive and some gram-negative bacteria and 

 fungi. Active on M. tuberculosis H37Rv and BCG 

 at 0.16 Mg per ml. No cross-resistance between 

 streptovaricin and the major antibiotics is ob- 

 served in micrococci. Development of resistance 

 follows two patterns, one fast, the other slow, de- 

 pending on the component and the organism used. 



No cross-resistance between components. Com- 

 ponents A and B more active than C on M. ranae, 

 but all are equally active against B. subtilis. A 

 and B also active on certain gram-negative bac- 

 teria and fungi. D and E have no activity on 

 gram-negative bacteria and only slight activity on 

 gram-positive bacteria and mycobacteria. In vivo: 

 Complex is active against M. tuberculosis var. 

 hominis H37Rv and M. tuberculosis var. bovis 

 (Vallee) in mice and guinea pigs. Streptovari- 

 cin-sensitive, virulent, acid-fast bacilli can be 

 isolated from tissues of streptovaricin-treated, 

 surviving mice that show no gross lesions. In my- 

 cobacteria, development of resistance to strepto- 

 varicin is accompanied by reduction of virulence 

 to mice. Active on murine leprosy. Component A 

 has no antimycobacterial activity in vivo; C has 

 more than the complex (1, 3-5, 8). 



Toxicity: Mice tolerate 1000 mg per kg per day 

 by oral intubation, and 800 mg per kg per day sub- 

 cutaneously for 6 days (3). 



References: 



1. Siminoff, P. et al. Am. Rev. Tul)erc. 75: 



576-583, 1957. 



2. Whitfield, 0. B. ct al. Am. Rev. Tuberc. 



75: 584-587, 1957. 



3. Rhuland, L. E. et al. Am. Rev. Tuberc. 75: 



588-593, 1957. 



4. Sokolski, W. T. et al. Antibiotics Ann. 1957- 



1958, pp. 119-125. 



5. Karlson, A. G. Proc. Staff Meeting Mayo 



Clinic 33: 193-196, 1958. 



6. Nathan, A. Trans. 17th Veterans Admin. 



Conf. Chemotherapy Tuberc, pp. 336-338, 

 1958. 



7. Herr, R. R. et al. Abstr. 134th Meeting Am. 



Chem. Soc. 21 O, 1958. 



8. Chang, V. T. Am. Rev. Tuberc. 79: 673- 



676, 1959. 



9. Garrett, E. R. J. Am. Pharm. Assoc, Sci. 



Ed. 48:169-176,1959. 



Streptovitacins 



Produced by: Streptoniyces griseus. This culture 

 also produces cycloheximide. 



Remarks: Streptovitacins A and B are isomeric 

 hydroxylated cycloheximide derivatives (3). 



Method of extraction: Whole culture adjusted to 

 pH 3.5, heated to 60°C, cooled, and filtered. Cyclo- 

 heximide and other constituents removed by ex- 

 traction of filtrate with chloroform or methylene 

 chloride. Streptovitacins adsorbed on carbon and 

 eluted with acidic aqueous 85 per cent acetone. 

 Eluate concentrated by vacuum distillation. Resi- 

 due adsorbed on Permutit DR from aqueous solu- 



