Antibiotics from microbispora

Details Antibiotics from microbispora Antibiotics from microbispora

2001-09-07

2003-04-22

Lilling, Herbert J. (Department: 1651)

Drug, bio-affecting and body treating compositions

Fermentate of unknown chemical structure

C435S071300, C435S252100

Reexamination Certificate

active

06551591

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the fields of chemistry, bacteriology, biology, biochemistry, pharmacology and medicine. In particular it relates to two new antibiotics isolated from a fermentation broth of a novel strain of
Microbispora corallina.
BACKGROUND OF INVENTION
Over the past 60 years, a broad range of antibiotics, have become available for the treatment and prevention of bacterially transmitted disease. Penicillin, streptomycin, aureomycin, cephalosporin, bacitracin, erythromycin, novobiocin, methicillin, neomycin, chloramphenicol, kanamycin, chlortetracycline,to name a few—each of these drugs, isolated from microorganisms, has provided a great benefit to the well-being of people and animals the world around. Unfortunately, the widespread use of antibiotics, combined with the natural proclivity of target organisms to find a way to survive such attack, has resulted in an alarming increase in the number of resistant bacterial strains. This roster of resistant species includes a number of clinically important bacteria such as Staphylococcus, Salmonella, Enterobacteriaceae and Pseudomonas, in particular, the species
S. aureus
and
S. pneumoniae
. Thus, there continues to be an urgent need for new drugs, exhibiting novel modes of action unrecognized by target organisms, to overcome the resistance of these and other species of bacteria.
While a great deal of effort is being expended to design new, partially or entirely synthetic drugs to fill the voids in therapeutic efficacy created by the emergence of resistance, nature continues to be a invaluable source of such compounds.
SUMMARY OF THE INVENTION
Thus, the present invention relates to two antibiotics designated MF-BA-1768&agr;
1
and MF-BA-1768&bgr;
1
, to their production by fermentation, to methods for their recovery and concentration from fermentation broth, and to processes for their purification. It includes within its scope the antibiotics in dilute form, in crude concentrates, in complexes of various or all components, and in pure form as individual compounds. The present invention also includes a novel strain of
Microbispora corallina
, which produces the compounds. The strain is identified by the DNA sequence that codes for its partial 16S rRNA sequence and by its nutrient utilization pattern. The chemical structures of the new antibiotics are presently unknown but four potential structural features have been deduced based on partial 2-D NMR data including
1
H—
1
H correlation (COSY) and
1
H—
13
C correlation (HMQC). The compounds are characterized by their physical and chemical properties including UV, IR, and
1
H NMR spectra. Their molecular weights were determined by ESI-FTMS.
In one aspect, this invention relates to antibiotic MF-BA-1768&agr;
1
, or a pharmaceutically acceptable salt thereof, having the physicochemical characteristics, in the non-salt form, described in detail below.
In another aspect, this invention relates to antibiotic MF-BA-1768&bgr;
1
, or a pharmaceutically acceptable salt thereof, having the physicochemical characteristics, in the non-salt form, described in detail below.
In a further aspect, this invention relates to a process for producing antibiotic MF-BA-1768&agr;
1
, comprising cultivating a strain of
Microbispora corallina
, NRRL 30420, or an antibiotic MF-BA-1768&agr;
1
-producing mutant, variant or recombinant form thereof, in a culture medium containing assimilable sources of carbon, nitrogen and inorganic salts under aerobic fermentation conditions until antibiotic MF-BA-1768&agr;
1
, is produced and then recovering the antibiotic therefrom.
In a still further aspect, this invention relates to a process for producing antibiotic MF-BA-1768&bgr;
1
, comprising cultivating a strain of
Microbispora corallina
, NRRL 30420, or an antibiotic MF-BA-1768&bgr;
1
-producing mutant, variant or recombinant form thereof, in a culture medium containing assimilable sources of carbon, nitrogen and inorganic salts under aerobic fermentation conditions until antibiotic MF-BA-1768&bgr;
1
, is produced and then recovering the antibiotic therefrom.
An aspect of this invention is a biologically pure culture of
Microbispora corallina
, NRRL 30420, or an antibiotic MF-BA-1768&agr;
1
-producing mutant, variant or recombinant form thereof.
An aspect of this invention is a biologically pure culture of
Microbispora corallina
, NRRL 30420, or an antibiotic MF-BA-1768&bgr;
1
-producing mutant, variant or recombinant form thereof.
A bacterial strain comprising DNA SEQ. No. 1, or a sequence having at least 80% homology therewith, is an aspect of this invention.
An aspect of this invention is a pharmaceutical composition comprising a therapeutically effective amount of compound MF-BA-1768&agr;
1
and a pharmaceutically acceptable carrier, wherein compound MF-BA-1768&agr;
1
has the physicochemical characteristics described in detail below.
An aspect of this invention is a pharmaceutical composition comprising a therapeutically effective amount of compound MF-BA-1768&bgr;
1
and a pharmaceutically acceptable carrier, wherein compound MF-BA-1768&bgr;
1
has the physicochemical characteristics described in detail below.
An aspect of this invention is a method for treating a bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of compound MF-BA-1768&bgr;
1
, which has the physicochemical characteristics described in detail below.
An aspect of this invention is a method for treating a bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of compound MF-BA-1768&bgr;
1
, which has the physicochemical characteristics described in detail below.
A further aspect of this invention is either of the preceding two methods wherein the infection-causing bacteria are from the genera Staphylococcus, Enterococcus, Streptococcus, Haemophilus or Escherichia.
An aspect of this invention is the above methods wherein the infection-causing bacteria are
Staphylococcus aureus, Staphylococcus epidermis, Staphlyococcus haemolyticus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyrogenes, Haemophilus influenzae
or
Eschericia coli.
DETAILED DESCRIPTION OF THE INVENTION
Brief Description of the Tables
Table 1 is a list of the cultural characteristics of
Microbispora corallina
strains MF-BA-1768, JCM 12066, and JCM 12067.
Table 2 is a carbon source utilization listing for
Microbispora corallina
strains MF-BA-1768, JCM 12066, and JCM 12067


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patent: 5484717 (1996-01-01), Zaccardi
patent: 6187568 (2001-02-01), Nishida et al.
Argoudelis, et al, “Argoudelis, Application of”, (Cust & Pat. App. 19700 434 F.2d 1390.
Lee, Ving J., et al., “Efflux-Mediated Resistance to Antibiotics in Bacteria: Challenges and Opportunities”,Current literature: Antibacterial Research, vol. 2, No. 2, 1998, pp. 39-42.
Aoyagi, T., et al. “Benastatins A and B. New Inhibitors of Glutathione S-Transferase, Produced by Streptomyces so. MI384-DF12”,The Journal of Antibiotics, vol. 45, No. 9, Sep. 1992, pp. 1385-1396.
Li, Xian-Zhi, et al., “Role of Efflux Pump(s) in Intrinsic Resistance ofPsedomonas aeruginosa: Resistance to Tetracycline, Chloramphenicol, and Norfloxacin”,Antimicrobial Agents and Chemotherapy, vol. 38, No. 8, Aug. 1994, p. 1732-1741.
Sahl, H., et al., “Lantibiotics: Biosynthesis and Biological Activities of Uniquely Modified Peptides from Gram-Positive Bacteria”,Annual Reviews, 1998, 52:41-79.

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