180 



DESCRIPTIONS OF ANTIBIOTICS 



Ac tin oxaii thine 



Produced by: Sireptomyces globisporus (3). 



Method of extraction: Antibiotic salted out of 

 broth-filtrate with (NH4)jS()4 . Precipitate dis- 

 solved in water and reprecipitated successively 

 with (NH4)2S04 . Chromatographed on AI2O3 ■ 

 Elution with water, acidification of active frac- 

 tions to precipitate impurities, concentration, 

 treatment with ion exchange resins, and precipi- 

 tation of excess CO3" with BaS()4 . Solution con- 

 centrated to dryness (1, 2). 



Chemical and physical properties: Water-solu- 

 ble, proteinaceous or peptide-like substance (1). 

 Inactivated by air in dry form; more stalile in 

 ar[ueous solution (2). 



Biological activity: Very active on gram-positive 

 bacteria and tumors, including Ehrlich adeno- 

 carcinoma. No cross-resistance with penicillin, 

 streptomycin, or chlortetracycline (1, 2). Active 

 on cotton gummosis (4). 



Toxicity: Maximal tolerated doses in mice 

 (single administration): intraperitoneally, 0.025 

 mg per kg; intravenously, 0.023 mg per kg; sul)- 

 cutaneously and intramuscularly, 1.2 mg per kg; 

 orally, 19.5 mg per kg (5). 



References: 



1. Buyanovskaya, I. vS. e/ o/. Antibiotiki 2(1): 



17-20, 1957. 



2. Vikhroba, N.M.e^a/. Antibiotiki 2(1): 21- 



25, 1957. 



3. Solovieva, N. K. and Delova, I. D. J. Mi- 



crobiol. Epidemiol. Immunobiol. 29: 399- 

 404, 1958. 



4. Starygina, L. P. et al. quoted in Rautensh- 



tein, Y. I. Mikrobiologiya 28: 146-151, 

 1959. 



5. Vieis, R. A. Antiljiotiki 3(1): 22-27, 1958. 



Actithiazic Acid 



Produced by: Streptotnyces sp. re.sembling S. 

 lavendulae (1), *S. virginiae (2), S. acidomyceticiis 

 (7), S. cinnamonensis (9), S. lydiciis (13), and S. 

 roseochromogenes (14) . 



Synonyms: Antibiotic PA 95 (15), mycobacidin 

 (1), acidomycin (7), cinnamonin (9), thiazolidone 

 antiliiotic (12). 



Method of extraction: I. Broth-filtrate ex- 

 tracted with n-butanol or butyl acetate at pH 

 2.0. Back-extracted into Na^COs solution. Ex- 

 tract adjusted to pH 4.5, then repeatedly ex- 

 tracted with butyl acetate. Butyl acetate evapo- 

 rated, residue taken up in hot ethylene dichloride, 

 treated with activated carbon, and filtered. 

 Crystals form on cooling. Recrystallization from 

 hot water, warm acetone, or methanol (4, 7, 14). 

 II. Adsorbed from broth-filtrate on carbon. 



Eluted with ethanol -methanol (95:5) or 50 per 

 cent aqueous acetone at pH 7.0, 50°C. Eluate ad- 

 justed to pH 8.0, filtered, and concentrated under 

 reduced pressure. Concentrate extracted with 

 butanol at pH 3.0, or with ethyl acetate at pH 

 1.0 to 2.0. Purified by chromatography on (a) 

 silica gel with butanol as solvent and developer; 

 active fractions washed with water at pH 2.0, 

 concentrated and cooled to give a precipitate 

 (5); or (b) alumina and developed with ethyl 

 acetate, acetone, 1 per cent Ba(OH)2 , and 4 per 

 cent NaOH, successively. Recrystallized from 

 ethanol (10) IRA-400 and eluted with 10 to 20 

 per cent ammonium chloride. Eluate adjusted to 

 pH 4.5 and freeze dried. Crystallized from chloro- 

 form with hexane. A hot ethylene dichloride solu- 

 tion of precipitate filtered through charcoal and 

 cooled to give crystals. Recrystallized from 

 methanol, and then water or ethvlene dichloride 

 (14). 



Chemical and physical properties: Monobasic 

 acid. Colorless needles; m.p. 137.5-141 °C (1, 4, 5, 

 7, 10). Soluble in dilute NaOH, lower alcohols, 

 ethyl acetate, benzyl alcohol, and hot water. 

 Less solul)le in acetone and distilled water. Very 

 slightly soluble or insoluble in ether, ethylene 

 dichloride, benzene, chloroform, petroleum ether, 

 and water (5, 10). [a]'^ = —60.5° (c = 1 i)er cent 

 in absolute ethanol). End-absorption in ultra- 

 violet light (5). Blue fluorescence in ultraviolet 

 light (7). Infrared spectrum given in reference 

 5. pKa' = 5.8. Negative 2,4-dinitrophenylhydra- 

 zine, Tollen, ninhydrin, and FeCls tests (10). 

 Positive bromine and KMn04 tests. A strongly 

 alkaline solution heated with lead acetate dark- 

 ens, with evolution of NH3 . Forms a white pre- 

 cipitate with HgClo . Stable (4). C9Hi50.,NS (5, 

 10). C = 49.86%; H = 6.86%; N = 6.46%,; S = 

 14.4%. No C — CH3 . Actithiazic acid is 4-thiazoli- 

 done-2-caproic acid (5, 6). Structural formula is 

 given in Chapter 6. Forms biologically active 

 esters. Methyl actithiazate: Colorless needles; 

 m.p. 53-54°C. [a]l = -50.9 (c = 1 per cent in 

 methanol) (6). Oxidation with H2O2 yields pimelic 

 acid (5); with HNO3 , adipic acid (7). 



Biological activity: Active principally on myco- 

 bacteria and nocardiae; not active on other bac- 

 teria (2). Not active on tuberculosis infections in 

 mice (3, 7). Activity reversed by biotin. Inter- 

 feres with biotin synthesis in mycobacteria (2, 

 11). A number of esters formed by actithiazic 

 acid are about twice as active as the parent com- 

 pound on mycobacteria (6). The Na salt, methyl 

 and ethyl esters, the hydrazide, and amide and 

 guanidine derivatives of the antibiotic are active 

 in vitro on mycobacteria (8). 



