Nocathiacin antibiotics

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C540S450000

Reexamination Certificate

active

06218398

ABSTRACT:

BACKGROUND
The emergence of bacterial resistance to a number of antimicrobial agents such as beta-lactam antibiotics, macrolides, quinolones, and vancomycin is becoming a major worldwide health problem. (Cohen, M. L. Antimicrobial resistance: prognosis for public health.
Trends Microbiol
. 1994, 2, 422-425). The most significant problem in clinical practice is the increase in incidence of methicillin-resistant
Staphylococcus aureus
(MRSA) strains. At present, the only effective treatment for multiple resistant MRSA infections is vancomycin. However, there are recent reports of emerging vancomycin resistance in some MRSA isolates. Another group of clinically relevant multiple drug resistant bacteria that have emerged recently are the Enterococci. The emerging resistance of the important community acquired pathogen
Streptococcus pneumoniae
to penicillin and other antibacterials is also becoming a worldwide health problem. Multi drug-resistant strains of
Mycobacterium tuberculosis
have surfaced in several countries including the United States. The emergence and spread of resistant nosocomial and community-acquired pathogens is generating a great threat to public health worldwide. There is an urgent need to discover new agents to treat patients infected with multidrug-resistant bacteria. The present invention addresses this need.
New thiazolyl peptide antibiotics, (designated herein as nocathiacin I, II and III, or collectively as nocathiacin) having inhibitory activity at the nanomolar level against Gram-positive bacteria (e.g. multiple drug resistant
Enterococcus faecium
), are described. The novel antibiotics described herein were isolated from cultured broth of Nocardia sp. ATCC-202099. Known members of the thiazolyl peptide class of antibiotics such as thiostrepton and nosiheptide, and glycothiohexide-&agr; have been reported to exhibit potent antimicrobial activity against Gram-positive bacteria in vitro, with no reported activity in vivo. The novel antibiotics disclosed herein exhibit in vivo efficacy in a systemic
Staph. aureus
infection model in mice.
Nocathiacin I has been previously described by J. E. Leet et al (U.S. Provisional Patent Application Serial No. 60/093,021 filed Jul. 16, 1998) commonly owned by Applicant herein, and Sasaki, T. et al,
J. of Antibiotics
51, No. 8, pp. 715-721 (published Aug. 25, 1998). The novel nocathiacin antibiotics of this invention 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); glycothiohexides (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).
SUMMARY OF THE INVENTION
The invention concerns novel thiazolyl peptide antibiotic compounds nocathiacin I, II and III. The antibiotics of this invention can be isolated and purified from Nocardia sp. (strain WW-12651, ATCC-202099) fermentation broths.
The invention also deals with pharmaceutical compositions and methods for treating bacterial infections with nocathiacin I, II and III antibiotics, as well as a biologically pure culture of Nocardia sp. strains from which the antibiotics are obtained. The invention includes all pharmaceutically acceptable derivatives of nocathiacin antibiotics, such as pharmaceutically acceptable salts and esters thereof.
The utility of the subject compound 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 mammals, 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.
Cohen, “Antimicrobial resistance: prognosis for public health,”Trends in Microbiology, vol. 2, No. 10, Oct. 1994, pp. 422-425.
Sasaki, et al., “MJ347-81F4 A & B, Novel Antibiotics fromAmycolatopsissp.: Taxonomic Characteristics, Fermentation, and Antimicrobial Activity,”Journal of Antibiotics, vol. 51, No. 8, 1998, pp. 715-721.
Pascard, et al., “Highly Modified Cysteine-Containing Antibiotics. Chemical Structure and Configuration of Nosiheptide,”J. Am. Chem. Soc., 99, 1977, pp. 6418-6423.
Benazet, et al., “Nosiheptide, a sulfur-containing peptide antibiotic isolated fromStreptomyces actuosus40037,”Experientia, 36, 1980, pp. 414-416.
Mocek, et al., “Biosynthesis of the Modified Peptide Antibiotic Nosiheptide inStrptomyces actuosus,”Journal of the American Chemical Society, vol. 115, No. 17, Aug. 25, 1993, pp. 7557-7568.
Steinberg, et al., “Glycothiohexides, Novel Antibiotics Produced by”Sebekia“sp. LL-14E605. I. Taxonomy, Fermentation and Biological Evaluation,”Journal of Antibiotics, vol. 47, No. 8, Aug. 1994, pp. 887-893.
Northcote, et al., “Glycothiohexide &agr;, A Novel Antibiotic Produced by”Sebekia“sp. LL-14E605. II. Isolation and Physical-chemical Characterization,”Journal of Antibiotics, vol. 47, No. 8, Aug. 1994, pp. 894-900.
Northcote, et al., “Glycothiohexide &agr;, A Novel Antibiotic Produced by”Sebekia“sp. LL-14E605. III. Structural Elucidation,”Journal of Antibiotics, vol. 47, No. 8, Aug. 1994, pp. 901-908.

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