Drug – bio-affecting and body treating compositions – Fermentate of unknown chemical structure
Reexamination Certificate
1999-08-10
2001-05-01
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Fermentate of unknown chemical structure
C424S117000, C435S128000, C435S130000
Reexamination Certificate
active
06224864
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention concerns cytosine-containing antibiotic 10381a
1
and antibiotics 10381b, which are obtained by the fermentation of a nutrient medium with a new species of Streptomyces,
Streptomyces arginensis.
Antibiotics 10381b comprise a group of at least five antibacterial agents active mainly against G-positive organisms and having physical properties similar to those reported for the sulfomycin group of antibiotics.
2. Information Disclosure
Cytosine-containing antibiotics are known in the art. The nucleoside antibiotic gougerotin is disclosed in J. J. Fox et al., Tetrahedron Letters, No. 57, pp. 6029-6032 (1968). The antibiotics amicetin, plicacetin and bamicetin are disclosed in T. H. Haskell et al., J. Amer. Chem. Soc., 80:743-747 (1958). The antibiotics amicetin and bamicetin are also disclosed in C. L. Stevens et al., J. Org. Chem., 31:2822-2828 (1966). The antibiotic blasticidin S is disclosed in H. Yonehara and N. Otake, Tetrahedron Letters, 32:3785-3791 (1966) and in H. Seto and H. Yonehara, The J. of Antibiotics, XXX (11):1022-1024, November 1977.
None of the prior art antibiotics known to Applicant teaches or suggests antibiotic 10381a
1
. In addition, there are accordingly unexpected and advantageous properties associated with this new antibiotic 10381a
1
, e.g., greatly reduced toxicity.
The production and properties of arginomycin (antibiotic 10381a
1
) are described in International Application, PCT/US86/00657 (International Publication Number WO86/05785 dated Oct. 9, 1986), and in A. D. Argoudelis et al., The Journal of Antibiotics, XL 6):750-760, June 1987.
The production and properties of antibiotics 10381b are described in International Application PCT/US87/01450 (International Publication Number WO 88/00200 dated Jan. 14, 1988.
Streptomyces arginensis
(Culture 10381) also produces a mixture of solvent-soluble compounds useful as antibiotics against Gram-positive organisms including “resistant”
Staphylococcus aureus.
These antibiotics have been designated as 10381b antibiotics. The present invention describes the production, isolation and physical and biological properties of antibiotics 10381b.
Chemically, antibiotics 10381b appear to be related to the sulfomycins, which are reported to be peptides of unknown structure. See Y. Egawa et al., “Sulfomycins, A Series of New Sulfur-Containing Antibiotics. I: Isolation, Purification and Properties.” J. Antibiotics, 22:12-17 (1969).
As part of an effort to elucidate the relationship between antibiotics 10381b and the sulfomycins, the antibiotic production patterns of
S. arginensis
and two sulfomycin-producing cultures were compared under the fermentation conditions developed for production of antibiotics 10381b. The three cultures produce activities which appear virtually identical when analyzed by the methods used for antibiotics 10381b. However, only
S. arginensis
produces antifungal activity (antibiotic 10381a
1
/arginomycin).
Sulfomycins produced by
Streptomyces viridochromogenes
ss
sulfomycini
ATCC 29776; UC 8410 were isolated by procedures used for the isolation of the antibiotic 10381b complex. The obtained material was compared to the antibiotic 10381b complex by infrared spectra (IR), ultraviolet spectra (UV), paper chromatography, thin layer chromatography (tlc), high performance liquid chromatography (HPLC) and antibacterial spectra. It appears that antibiotics 10381b are very similar, if not identical, to the sulfomycins. Antibiotic 10381b
2
, the main antibiotic, is almost identical to the main activity produced by the sulfomycin-producing organisms, and all indications are that it is Sulfomycin I, which is known in the art, as discussed below. However, the producing organisms are definitely different.
S. arginensis
(culture 10381) produces arginomycin, while the two sulfomycin-producing cultures do not produce arginomycin or any other antifungal activity.
U.S. Pat. No. 4,007,090 discloses and claims a novel fermentation process for the preparation of sulfomycin from the microorganism
Streptomyces cineroviridis.
Sulfomycin I is a known Gram-positive antibiotic described in Japan Pat. No. 45-6880 (Derwent Abstract, Accession Number 18445R). Sulfomycin II and III are also described in the literature as Gram-positive antibiotics in Japan Pat. publication No. 17599/1970 (Derwent Abstract, Accession Number 42550R). All three Sulfomycin antibiotics were prepared by the fermentation of a strain of the microorganism
Streptomyces viridochromogenes.
SUMMARY OF THE INVENTION
This invention concerns cytosine-containing antibiotics of formula I wherein R is hydrogen or an alkyl of 1 to 3 carbon atoms, inclusive. The compounds are active in vitro against Gram-positive bacteria, yeasts, and fungi. The compounds are particularly active against
Candida albicans
(UC® 1392),
Penicillium oxalicum
(UC 1268), and
Saccharomyces cerevisiae
(UC 1342) and have a low toxicity in mammals. (UC is a registered trademark of The Upjohn Company). Specifically this invention concerns both a pure form of a naturally occurring cytosine-containing antibiotic named 10381a
1
and synthetically derived alkyl esters. In addition, the invention includes a process for culturing and purifying 10381a
1
.
The present invention also provides:
A process for the preparation of Antibiotics 10381b which comprises: fermenting with a strain of
Streptomyces arginensis,
NRRL 15941 and mutants thereof, an aqueous nutrient medium containing an assimilable source of carbon and an assimilable source of nitrogen under aerobic conditions;
A method for promoting growth in meat-producing animals which comprises: administering to the animals an amount of antibiotics 10381b effective to promote growth; and
A biologically pure culture of the microorganism
Streptomyces arginensis,
characterized as being essentially the strain identified as NRRL-15941.
The antibiotics of the present invention are produced by a naturally occuring microorganism. As such, these antibiotics may be produced by this organism as it exists in its natural state. The present invention as it is directed to these antibiotics does not encompass any composition thereof as might have or does exist or occur in nature. Rather, the present invention provides for the production and isolation of these antibiotics in a manner rendering them practically useful, e.g., for pharmacological and other anti-microbial purposes.
Accordingly, the antibiotics described herein can be used alone or in combination with other antimicrobial agents to prevent the growth or reduce the numbers of microorganisms in various environments. For example, the compounds could be used to disinfect surfaces or as an additive to paint to prevent excess growth of microorganisms.
DETAILED DESCRIPTION
Antibiotics of formula I where R is hydrogen are obtainable from the cultivation of
S. arginensis.
This antibiotic is designated 10381a
1
. The taxonomy of the organism is given below. The extraction, purification and physicochemical analysis of this antibiotic are also described below.
Compound 10381a
1
has broad spectrum antibiotic properties having an especially strong growth inhibitory effect upon yeasts and fungi. In addition, 10381a
1
has less toxicity than blasticidin, a known antibiotic of similar structure.
Antibiotics 10381b of the present invention are also obtainable from the cultivation of
S. arginensis.
The taxonomy of the organism is given below.
Microorganism
The microorganism used for the production of antibiotic 10381a
1
and antibiotics 10381b is a new species of streptomyces,
Streptomyces arginensis
Dietz sp., NRRL-15941. The organism was isolated from soil screening conducted by The Upjohn Company and was taxonomically characterized by Alma Dietz of The Upjohn Company. A subculture of the organism was deposited under the provisions of the Budapest Treaty on Mar. 8, 1985 in the permanent collection of the Northern Region Research Center, ARS; U.S. Dept. of Agriculture; Peoria, Ill., USA. Its accession number is NRRL-15941.
Col
Argoudelis Alexander D.
Argoudelis Cassandra
Laborde Alice L.
Sebek Oldrich K.
Shilliday Franklin B.
Argoudelis Cassandra
Goldberg Jerome D.
Pharmacia & Upjohn Company
Thomas A. Wootton Pharmacia & Upjohn
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