Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2000-05-01
2001-09-11
Weber, Jon P. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S041000
Reexamination Certificate
active
06287827
ABSTRACT:
BACKGROUND OF THE INVENTION
Multidrug-resistant strains of many clinically important pathogenic bacteria, including methicillin-resistant
Staphylococcus aureus
(MRSA),
Streptococcus pneumoniae, Mycobacterium tuberculosis
, and Enterococci strains are becoming a worldwide health problem. There is an urgent need to discover new agents to treat patients infected with multidrug-resistant bacteria. A new group of thiazolyl peptide antibiotics, (designated herein as nocathiacins) having inhibitory activity at the nanomolar level against Gram-positive bacteria has been discovered. The present invention relates to novel antibiotic halo- or hydroxy-substituted nocathiacin compounds, and comprising the process for preparing them by precursor-directed biosynthesis with Nocardia sp. ATCC-202099 or mutants thereof. The novel nocathiacin antibiotics disclosed herein exhibit potent antimicrobial activity against Gram-positive bacteria in vitro, and exhibit in vivo efficacy in a systemic
Staph. aureus
infection model in animals. The nocathiacin compounds are antibiotics useful in the treatment of bacterial infections in humans.
PRIOR ART
The substituted nocathiacin antibiotic compounds of this invention are produced by Nocardia sp. ATCC-202099 in a novel fermentation process. This microorganism also produces nocathiacin I and II, which were previously described by J. E. Leet et al (U.S. Provisional Patent Application Serial No. 60/093,021 filed Jul. 16, 1998) and Sasaki, T. et al,
J. of Antibiotics
51, No. 8, pp. 715-721 (1998). The nocathiacin antibiotics are related to but clearly distinguishable from nosiheptide (Prange T. et al.,
J. Am Chem Soc
. 99, 6418 (1977); Benazet, F. et. al.
Experientia
36, 414 (1980); Floss, H. G. et al.,
J. Am Chem Soc
. 115, 7557 (1993); glycothiohexide-a (Steinberg, D. A. et al, J. Antibiot. 47, 887 (1994); M. D. Lee et al,
J. Antibiot
. 47, 894 (1994); M. D. Lee et al,
J Antibiot
. 47, 901 (1994); U.S. Pat. No. 5,451,581, 1995), and Antibiotic S-54832A (U.S. Pat. No. 4,478,831, 1984). Nocathiacin I (R is OH) and II (R is H) are indicated by the formula
SUMMARY OF THE INVENTION
The invention concerns novel antibiotic compounds of Formula IV, or pharmaceutically acceptable salts thereof, which are halo- or hydroxy-substituted nocathiacins produced by precursor-directed biosynthesis with nocathiacin antibiotic producing microorganisms. Specifically, 5-fluoronocathiacin is obtained by the fermentation of Nocardia sp. ATCC-202099 or mutants thereof, in the presence of 5-fluorotryptophan. The fermentation process is accomplished under submerged aerobic conditions in an aqueous medium containing carbon and nitrogen nutrient at a pH of about 5-8 for a sufficient time to produce 5-fluoronocathiacin. The resulting antibiotics exhibit improved antibiotic activity against a broad spectrum of Gram-positive bacteria, compared to nocathiacin I or II.
The invention also deals with pharmaceutical compositions and methods for treating bacterial infections with the novel nocathiacins, as well as a biologically pure culture Nocardia sp. ATCC-202099 from which the antibiotic is obtained.
The utility of the subject compounds in the treatment of bacterial infections is based upon the expectation that compounds which inhibit Gram-positive bacteria in vitro and in vivo can be used as antibiotics in animals, and in particular, humans. The compounds of this invention were found to have antibiotic activity, particularly in inhibiting the growth of Gram-positive bacteria.
REFERENCES:
patent: 4478831 (1984-10-01), Keller-Juslen et al.
patent: 5451581 (1995-09-01), Lee et al.
patent: WO 00/03722 (2000-01-01), None
T. Sasaki, et al, J. of Antibiotics, 51(8), pp. 715-721, 1998.
C. Pascard, et al, J. Am. Chem. Soc., 99(19), pp. 6418-6423, 1977.
F. Benazet, et al, Experientia, 36, pp. 414-416, 1980.
U. Mocek, et al, J. Am. Chem. Soc., 115(17), pp. 7557-7568, 1993.
D. A. Steinberg, et al, J. Antibiotics, 47(8), pp. 887-893, 1994.
P. T. Northcote, et al, J. Antibiotics, 47(8), pp. 894-900, 1994.
P. T. Northcote, et al, J. Antibiotics, 47(8), pp. 901-908, 1994.
M. Lee and R. S. Phillips, “Synthesis and Resolution of 7-Fluorotryptophans,” Bioorg. Med. Chem. Lett., 1(9), pp. 477-480, 1991.
E. D. Bergmann and E. Hoffman,, “6-Fluoro-, 6-Methoxy-, and 7-Methoxy-Tryptophan,” J. Chem. Soc., pp. 2827-2829, 1962.
D. J. Hook, et al, J. Chromatography, 385, pp. 99-108, 1987.
Lam Kin S.
Leet John E.
Li Wenying
Bristol--Myers Squibb Company
DuBoff Samuel J.
Ozga Brett
Weber Jon P.
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