Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Bacteria or actinomycetales; media therefor
Reexamination Certificate
2001-10-11
2003-01-14
Marx, Irene (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
Bacteria or actinomycetales; media therefor
C435S125000
Reexamination Certificate
active
06506591
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a microbiological method for the manufacture of the antibiotic pseudomonic acid A (mupirocin).
BACKGROUND OF THE INVENTION
Pseudomonic acid A, also known as mupirocin, is an antibiotic that has a growth inhibiting effect mainly against Gram positive bacteria (e.g.
Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Klebsiella pneumoniae
) and some Gram negative bacteria (e.g.
Haemophilus influenzae, Neisseria gonorrhoeae
) [A. Ward, D. M. Campoli-Richards, Drugs 32, 425-444 (1986)] and its minimal inhibiting concentration is in the range of 0.02-0.5 mg/dm
3
. Pseudomonic acid A, by inhibiting the isoleucine-tRNA synthase enzyme, affects the peptide synthesis of pathogen bacteria [J. Hughes and G. Mellows, Biochem. J. 191, 209-219 (1980)]. An advantageous feature of this antibiotic is that it has very low toxicity both for humans and animals and it is negative in the Ames test. Pseudomonic acid A is presently used in human therapy, in various formulations, for the treatment of skin infections (e.g. impetigo, pyoderma), nose and external ear infections, acne, burns, eczema, psoriasis, in case of ulceration for treatment of secondary infections, and for prevention of hospital infections.
The chemical structure of pseudomonic acid A was determined to be 9-{4[5S(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-3R,4R-dihydroxy-tetrahydropyran-2S-yl]-3-methylbut-2(E)-enoyloxy}nonanoic acid [E. B. Chain and G. Mellows, J. C. S. Chem. Comm. 847-848 (1974); R. G. Alexander, J. P. Clayton, K. Luk, N. H. Rogers, T. J. King, J. C. S. Perkin I. 561-565 (1978)], as depicted by formula (I):
It is known that
Pseudomonas fluorescens
is able to produce the pseudomonic acid A. According to the British Patent No. 1,395,907, the
Pseudomonas fluorescens
NCIB 10586 strain is able to biosynthesize the pseudomonic acid complex consisting of pseudomonic acid A and its isomer being a double bond in the cis position between the carbon atoms C
2
and C
3
and pseudomonic acid B. The ratio of the components is 4.5:4.5:1. According to the Japanese patent application No. 52-70083, however, the
Pseudomonas fluorescens
Y-11633 strain is able to biosynthesize the pseudomonic acid complex consisting of the pseudomonic acid A, pseudomonic acid B and further two components with unknown structures in the ratio of 9:0.5:0.5.
SUMMARY OF THE INVENTION
The present invention is directed to a procedure for the preparation of pseudomonic acid A comprising cultivating on a medium comprising at least one organic nitrogen or carbon source, in submerged aerated conditions, a Pseudomonas bacterium strain capable of the biosynthesis of pseudomonic acid A, and fermentation of the Pseudomonas culture such that pseudomonic acid A is formed. Preferably the Pseudomonas bacterium strain is Pseudomonas sp. bacterium strain No. 19/26 deposited under accession No. NCAIM(P)B 001235 in the National Collection of Agricultural and Industrial Microorganisms, Budapest, Hungary, or its pseudomonic acid A-producing mutant or variant.
The present invention also is directed to a Pseudomonas culture capable of biosynthesizing pseudomonic acid A in submerged aerated conditions, consisting essentially of a novel Pseudomonas sp. bacterium strain No. 19/26.
The present invention further is directed to a biologically pure culture of a novel Pseudomonas sp. bacterium strain No. 19/26.
REFERENCES:
patent: 3977943 (1976-08-01), Barrow et al.
patent: 4071536 (1978-01-01), Barrow et al.
patent: 52070083 (1977-06-01), None
Mantle, et al., FEMS Microbiol. Lett. (1989), 59(1-2), 55-8.*
Feline, et al., J. Chem. Soc., Perkin Trans. 1 (1977), (3), 309-18.*
Feline et al. “Pseudomonic acid. Part 2. Biosynthesis of pseuomonic acid A.” Journal Chemical Society, Perkin Trans. I. 1977, pp. 309-318.
Mantle et al. “Radiolabelling of the monate moiety in the study of pseudomonic acid biosynthesis,” FEMS Microbiol. Lett. 1989, vol. 59, No. 12, pp. 55-58.
Martin et al. “Biosynthetic studies on pseudomonic acid (mupirocin), a novel antibiotic metabolite of Pseudomonas fluorescenes,” Journal Chemical Society Perkin Trans. I. 1989, pp. 207-209.
Ward et al. “Mupirocin—A review of Its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Use,” Drugs. 1986, vol. 32, No. 5, pp. 382-475.
Hughes et al. “Interaction of pseudomonic acid A withEscherichia coliB isoleucyl-tRNA synthetase.” Biochemical Journal. 1980, vol. 191, pp. 209-219.
Chain et al. “Structure of Pseudomonic Acid, an Antibiotic fromPseudomonas fluorescens.”Journal of the Chemical Society, Chemical Communications. Jan. 1974, No. 1, pp. 847-848.
Alexander et al. “The Chemistry of Pseudomic Acid. Part 1. The Absolute Configuration of Pseudomonic Acid A.” Journal of the Chemical Society, Perkin Transactions I, Organic and Bio-organic Chemistry. 1978, pp. 561-565.
Palleroni. “Psuedomonaceae.” Bergey's Manual of Systematic Bacteriology. 1984, vol. 1, pp. 141-219.
Albrecht Karoly
Balogh Gabor
Barta Istvan
Erdei Janos
Gulyas Eva
Biogal Gyogyszergyar Rt.
Kenyon & Kenyon
Marx Irene
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