Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-11-06
2001-05-08
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S050000, C435S071300, C435S252350
Reexamination Certificate
active
06228842
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the field of treatment of bacterial infections, and, in particular, to new pacidamycins.
The following description of the background of the invention is provided solely to aid in understanding the present invention. None of the references cited are admitted to be prior art to the present invention.
A number of different antibiotics with certain structural similarities to the compounds of this invention have been identified in publications and patents. These include the pacidamycins described by J. P. Karwowski et al, in
Journal of Antibiotics,
42:506-526, 1989. The mureidomycins described in U.S. Pat. No. 5,039,663 (Aug. 13, 1991) and by M. Inukai et al, in
Journal of Antibiotics
, Vol. 42:662-679, 1989 are related compounds containing a methionine moiety. Napsamycins, as described, for example, in European Patent Application publication number 0 487 756 A1 (Mar. 6, 1992) and by S. Chatterjee et al., in
Journal of Antibiotics,
47:595-598, 1994, are mureidomycins with a modified N-terminus. Additional related compounds are described in U.S. Pat. No. 4,180,564 (Dec. 25, 1979) and U.S. Pat. No. 4,499,075 (Feb. 2, 1985). These compounds, while not fully characterized, appear to be related to the mureidomycins or the pacidamycins based on their physical-chemical properties, chemical degradation products and biological properties.
All of the above references are incorporated herein by reference in their entireties, including any drawings.
SUMMARY OF THE INVENTION
The present invention concerns the identification of new pacidamycins and derivatives. These compounds were isolated from fermentation broths of
Streptomyces coeruleorubidus
NRRL 18730. Thus, the present invention concerns the new antibiotic compounds and derivatives of those and other uridyl peptide antibiotics compounds, methods of preparing those compounds, and the use of those compounds and compositions including those compounds to inhibit microbial growth, preferably bacterial growth or fungal growth.
Thus, in a first aspect, this invention provides enriched, isolated or purified antibiotic compounds identified herein as pacidamycin-D, pacidamycin-4N, pacidamycin-5N, and pacidamycin-5T, and derivatives of these compounds. This includes enriched preparations, such as those obtained by partial purification from fermentations of
Streptomyces coeruleorubidus
, NRRL 18730 or other strain producing one or more of these compounds.
The term “uridyl peptide antibiotic” refers to a compound having antibacterial and/or antifungal activity which includes a plurality of amino acid residues, preferably with 4, 5,or 6 amino acid residues, where the C-terminal amino acid is linked to the rest of the molecule through a urea group. The molecule has a uridine or uridine derivative group attached to one of the amino acid residues, preferably through a ribose=C—NHC(O)— linkage. A uridine derivative group may be substituted or modified on the sugar or on the base, for example, by the addition or removal of one or more hydroxyl groups. For example, the group may include a dihydrouracil group.
The terms “pacidamycin”, “mureidomycin”, and “napsamycin” refer to groups of uridyl peptide antibiotics as described in references cited herein. The “mureidomycins” are uridyl peptide antibiotics having a methionine residue linked to the urea group which is linked to the C-terminal amino acid. The “pacidamycins” are uridyl peptide antibiotics having an alanine residue linked to the urea group which is linked to the C-terminal amino acid. The “napsamycins” are similar to the mureidomycins, except they possess a substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid residue as the N-terminal amino acid.
Pacidamycin-D, pacidamycin-4N, pacidamycin-5N, and pacidamycin-5T are characterized and defined by the purification and physical and spectroscopic properties described below. The structures assigned are based on the physical and spectroscopic data, and are believed to be correct. However, in the event that the structural assignments are not fully correct, one skilled in the art will recognize that the compounds are fully identified by the purification and physical and spectroscopic data.
In connection with the compounds of this invention, the term “derivative” refers to compounds which retain the characteristic core structure of the corresponding base compound except that the C-terminal amino acid may be removed, modified, or replaced with another desired group, for example, a different amino acid. In particular, the term “derivative” includes the examples described by the generic description of compounds which may be derived from the CUPA compounds as described below.
In another aspect, the invention provides a uridyl peptide antibiotic derivative, e.g., a pacidamycin derivative, which has the carboxy terminal amino acid, modified, removed, or replaced with a different moiety. The compound resulting from removal of the C-terminal amino acid residue is termed a CUPA compound, for example, as shown in
FIG. 21
, or a corresponding molecule prepared by removal of the C-terminal amino acid from a different uridyl peptide antibiotic compound, preferably from a pacidamycin, more preferably from pacidamycin 1,4,5,6,D,4N,5N, or 5T, most preferably from pacidamycin D, 4N, 5N, or 5T. However, CUPA molecules can also be prepared from mureidomycins or napsamycins or other uridyl peptide antibiotic compounds. In general, the urea carbonyl through which the C-terminal amino acid is attached to the remainder to the molecule is preferably also removed. Such decarbonylation can be performed by standard methods.
In the context of CUPA compounds, the term “modification” in reference to the C-terminal amino acid means the attachment, removal, or alteration of one or more substituent groups on the C-terminal amino acid residue. Preferably this is performed by the removal of the original terminal amino acid and replacement with a modified form of the amino acid. In connection with the C-terminal amino acid modifications, the term “removal” refers to the cleavage of degradation of the C-terminal acid from the remainder to the molecule, and can also include the removal of the urea linkage carbonyl group. Also in connection with the C-terminal amino acid modifications, the term “replacement” refers to the attachment of a substituent group or moiety through the same atom as for the original C-terminal amino acid residue. Preferably the replacement group or moiety is also through a urea linkage, particularly where the replacement group or moiety is a different or modified amino acid. Thus, CUPA compounds can be used to provide additional derivatives of uridyl peptide antibiotic compounds.
In a related aspect, this invention provides pharmaceutical compositions which include pacidamycin-D, pacidamycin-4N, pacidamycin-5N, pacidamycin-5T, a CUPA compound, or derivatives of these compounds, preferably with a pharmaceutically acceptable carrier or excipient.
In another related aspect, this invention provides methods of using the above compounds to inhibit the growth of a microorganism, preferably a bacterium or a fungus. Such methods involves contacting such a microbe with at least one of the compounds pacidamycin-D, pacidamycin-4N, pacidamycin-5N, pacidamycin-5T, a CUPA compound, or derivatives of these compounds. The compound or compounds can be provided in the form of a pharmaceutical composition. The compound should preferably be provided such that the microorganism is contacted at a concentration above the MIC of the microorganism for the particular compound.
In another related aspect, the invention provides a method to treat an infection of an animal, preferably a mammal, by a microorganism, for example, by a bacterium or a fungus. The method involves administering to an animal suffering from such an infection a therapeutically effective amount of pacidamycin-D, pacidamycin-4N, pacidamycin-5N, pacidamycin-5T, a CUPA compound, or derivatives of these compounds.
Similarly, in a related aspect, the invention
Fronko Richard
Lee May
Lee Ving J.
Leger Roger
Lyon & Lyon LLP
Meller Michael V.
Microcide Pharmaceuticals, Inc.
Weber Jon P.
LandOfFree
Pacidamycins produced by Streptomyces coeruleorubidus does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pacidamycins produced by Streptomyces coeruleorubidus, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pacidamycins produced by Streptomyces coeruleorubidus will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2570147