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Aug. 17, 1965 3,201,386 Aug. 17, 1965 HiROSH KAWAGUCH ETA 3,201,386 COUMERMYCIN AND SALTS THEREOF Filed Aug. 25, 1964 Sheets-Sheet 6.25 EEE st H s 2OOO HillH HRH III- f HR &O S.O &C PER CENT TRANSMISSION HiROSH KAWAGUCH MASANOR OKANSH TAKEO MYAK INVENTORS BY CURTS W. CARLSON RCHARD H. BRINK HERBERT W., TAYLOR JR. ATTORNEYS Aug. 17, 1965 HiROSH KAWAGUCH ETAL 3,201,386 COUMERMYCIN AND SALTS THEREOF Filed Aug. 25, 1964 6 Sheets-Shee, 2 d O w | | o o a. 3. : Š 8 s 8ŠsŠs:ss;i HROSH KAWAGUCH MASANOR OKANSH TAKEO MYAK INVENTORS BY CURTS W. CARLSON RICHARD H. BRINK HERBERT W., TAYLOR JR. ATTORNEYS Aug. 17, 1965 HiROSH KAWAGUCH ETAL 3,201,386 COUMERMYCIN AND SALTS THEREOF Filled Aug. 25, 1964 6 Sheets-Sheet 3 l O C O He O3 H S cd O?) U U s 2 (d > 2Z to 2 Ch t u O O s a Hi-- (f). Z O 2 - C - 2. 9 or L 22 g a 39 st C is a s C On O l 2 PER CENT TRANS MSS ON HiROSH KAWAGUCH MASANOR OKAMSH TAKEO MYAK INVENTORS BY CURTS W. CARLSO N RCHARD H. BRINK HERBERT W. TAYLOR JR. ATTORMEYS Aug. 17, 1965 HiROSH KAWAGUCH ETAL 3,201,386 COUMERMYCIN AND SALTS THEREOF Filed Aug. 25, l964 6 Sheets-Sheet 4 d f C N w c N O - d O O ? y ?t) in " d O- 26 N 8 s O S O - M 2 2 in < 2 9 3. O (?o t - S a 2 to on ... O (f) ahamO 2.u d Z w 28 - & or 9H- is gog s 3 - 1 & ... O 2 S (V) () N. N O X C( > 1. Gig 8 CFRO co O C. Cd O l 2 PER CENT TRANS MSSION HiROSH KAWAGUCH MASANOR OKANISH TAKEO MYAK INVENTORS BY CURTS W. CARLSON RCHARD H. BRMK HERSERT W., TAYLOR JR. ATTORNEYS Aug. 17, 1965 HiROSH KAwAGUCH: ETAL 3,201,386 COUMERMYCIN AND SALTS THEREOF Filed Aug. 25, 1964 6 Sheets-Sheet 5 SNO.8D|VNNËH19N3TËEAVAA EEEEEEEEEEEEEEEEEEE| PER cent TRANsmission HiROSH KAWAGUCH MASANOR OKANSH TAKEO MYAK INVENTORS BY CURTS W. CARLSON RCHARD H. BRINK HERBERT W., TAYLOR JR. ATTORNEYS Aug. 17, 1965 HiROS - KAWAG c. A 3,20386 COUAERMYCIN AND SALTS THEREO Filed Aug. 25, 1964 W 6 Sheets-Sheet 6 o 3- S. s 8 s O 8 & 2 v O is on 5 T S. S. isw - 2 z d 2 O E 9 92 in: if f f 50 3. - g 2 . k.. 2 : 0 N. O 9 s l , g s S.al oga E C) 8 e o to t2. g 2 & 3 & PERCENT TRAN smission ROS- KAAAGUC NASANOR O CANS AKEO NYAK INVENTORS BY CRS W. CAR SON Ric-ARD H, SR NK HERBERT WAYOR R. AORNEYS 3,20,386 Patent Office Patented Aug. 17, 1965 and in N/10 NaOH having a maximum at 3,201,386 280 mu (E=766) HiroshiCOUMERMYCIN Kawaguchi, Masanori AND Okaaishi,SALTS THEREOF and Takeo Mii has a neutral equivalent of 548, has the following average yaki, Tokyo, Japan, assignors to Bristol-Banyu Re elemental analysis: C, 59.1%; H, 5.35%; N, 5.90% and O search institute, Ltd., Tokyo, Japan, a Japanese 5 (by difference), 29.65%; and when pelleted in potassium corporation bromide exhibits characteristic absorption in the infrared Filed Aug. 25, 1964, Ser. No. 392,003 region of the spectrum as shown in FIGURE 1; and salts 14 Clains. (Cl. 260-210) of said acidic substance. This invention relates to a new and useful substance Referring to the drawings: called coumermycin and to processes for its production. O FIGURE 1 is a curve of the infrared absorption spec More particularly, it relates to processes for its production trum of coumermycin free acid when pelleted in potas by fermentation and methods for its recovery and puri sium bromide. fication. The invention embraces this acidic antibacterial FIGURE 2 is a curve of the ultraviolet absorption agent and its alkaline salts in dilute solutions, as crude 5 spectrum of counermycin in solution in ethanol, in 0.1 concentrates, as purified solids and in pure crystalline N HCl and in 0.1 N NaOH. forms. Coumermycin is effective in inhibiting the growth FIGURES 3 and 4 taken together are the infrared ab of Gram-positive bacteria. Coumermycin is nontoxic and sorption spectrum of the monosodium salt of coumermy exhibits a therapeutic effect on mice infected with Gram cin A1 when pelleted in potassium bromide. postive bacteria. Coumermycin has also been called FIGURES 5 and 6 taken together are the infrared ab antibiotic Bu-620 and "Notomycin.” Coumermycin itself sorption spectrum of the monosodium salt of coumermy is a complex or mixture of five compounds which have cin A2. been given the individual names of coumermycin A1, There is further provided, according to the present in coumer mycin A2, coumermycin B, coumermycin C and vention, the process for the production of an antibiotic coumermycin D. substance, designated coumermycin, which comprises cul This application is a continuation-in-part of our prior tivating a strain of Streptomyces rishiriensis in an aqueous cope:Inding applications Serial No. 247,435, filed December carbohydrate solution containing a nitrogenous nutrient 17, 1962 and Serial No. 366,461, filed May 11, 1964 and under submerged aerobic conditions until substantial ac both now abandoned. tivity versus Gram-positive bacteria is imparted to said The most important members of the coumermycin 30 solution and then recovering said coumermycin from said complex are coumermyin A and coumermycin A which solution. have the formula The organism producing the antibiotic of the present C3 CH 3C O. O. O O O O CH itsc? -O IN O 4CH, 3CO OHI --NE-O Ö -NH HO d I E3 =0 NIH R wherein both R groups represent methyl in the case of invention was isolated from a sample of soil collected coumermycin A1 and represent hydrogen in coumermycin 45 in Rishiri Island, Hokkaido, Japan and is a new species, A2. The coumermycin complex is referred to herein designated Streptomyces rishiriensis of the genus Strep simply as coumermycin and is referred to in applicants' tomyces. A culture of the living organism, given the parent application Serial No. 247,435 simply as noto laboratory designations 404Y3 and A9795, has been de mycin. posited in the American Type Culture Collection, Wash There is now provided, according to the present inven- 50 ington, D. C. and added to its permanent collection of tion, an antibiotic substance effective in inhibiting the microorganisms as A.T.C.C. 14812. growth of Gram-positive bacteria which is selected from , the group consisting of an acidic substance, coumermycin, The representative strain, No. 404Y3 of S. rishiriensis which is readily soluble in acetone, dioxane and alkaline has the following characteristics: water, moderately soluble in ethanol, butanol, ethyl ace 5 5 CULTURAL CHARACTERISTICS tate, butyl acetate and methyl isobutyl ketone, less soluble G-growth; A-aerial mycelium; S-c soluble pigment; B-bio in benzene, methanoi and chloroform and insoluble in chemical property carbon tetrachloride, petroleum ether and acidic water, 1. Czapek's agar: which gives positive Fehling and Molisch reactions, de G: moderate, yellowish gray to light brownish gray colorizes bromine and gives negative ninhydrin, Tollens 60 or ivory yellow and anthrone reactions, and which in purified form melts A: poor, powdery, white at 222-224° C., exhibits (ox) D20 of -134 (c. = 1.0. ace S: none tone), exhibits an ultraviolet absorption spectra in ethanol 2. Glycerol Czapek's agar: having maxima at G: moderate, yellowish gray or light brownish gray 275 mu (E=595) 65 to pale yellow with faint brown and at - A: poor, powdery, white S: none or pale yellow with faint brown 335 mu (E4,-498) 3. Glycerol ammonium salt agar: in NA 10 HCl having maxima at G: moderate, light yellowish gray to yellowish white 275 mu (E=287) 70 A: scant, powdery, light yellowish gray to light gray and at 345 mp. (E=277) S: none 3,201,386 3 4. Glucose asparagine agar: 4. G: poor, thin, glossy, light yellowish gray branched hyphae, occasionally tuft, and sporophores A: none which produced sinistrorse spirals. On electron micro S: none Scopic observation, the shape of spores was found to be 5. Starch agar: elliptical to oval and the surface was smooth. G: good, light yellowish gray to ivory yellow 5 Streptomyces 404Y3 has a brownish gray aerial my A: moderate, powdery, spreading, faint brown to celium and produces brown or dark brown pigment on pale brown with gray organic media. Gelatin liquefaction is negative both in S: none gelatin stab and tyrosine yeast gelatin stab and milk is not B: hydrolysis is moderately strong digested. Nitrite is produced from nitrate and starch 6. Nutrient agar: 0 is hydrolyzed. Strain 404Y3 resenbles S. diastatochromo G: moderate, burnt umber to brown genes, S. griseoruber, S. olivochromogenes, S. aureus, S. A: poor, powdery, white griseochromogenes, S. haivaiensis and S. naganishi in S: dark brown some respects such as spiral formation, color of aerial 7. Bennett's agar: mycelium and nelanoid pigment, but differs in certain G: moderate, grayish olive brown to grayish brown cultural and physiological properties as shown below: A: moderate, white to pale brown to brownish gray S. diastatochromogenes.-According to Waksman and S: yellow brown Curtis, sporophores arc straight, and according to Jensen, 8. Oatmeal soyton agar: sinisrotrose spirals are produced. The color of aerial my G: good, pale yellow with faint brown celium is reported to be white to ash gray on Czapek's A: moderate, white to gray with faint brown 20 and gray on glucose asparagine agar.
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