Compounds

Details Compounds Compounds

2000-08-03

2002-10-15

Carlson, Karen Cochrane (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Proteins, i.e., more than 100 amino acid residues

C530S350000, C530S300000, C530S324000, C435S069700, C435S069100, C435S091400, C435S252300, C435S320100, C435S325000, C536S023100, C536S023700, C536S024300

Reexamination Certificate

active

06465621

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to newly identified polynucleotides and polypeptides, and their production and uses, as well as their variants, agonists and antagonists, and their uses. In particular, in these and in other regards, the invention relates to novel polynucleotides and polypeptides of the GTP-binding protein family, hereinafter referred to as “ERA”.
BACKGROUND OF THE INVENTION
It is particularly preferred to employ Staphylococcal genes and gene products as targets for the development of antibiotics. The Staphylococci make up a medically important genera of microbes. They are known to produce two types of disease, invasive and toxigenic. Invasive infections are characterized generally by abscess formation effecting both skin surfaces and deep tissues.
S. aureus
is the second leading cause of bacteremia in cancer patients. Osteomyelitis, septic arthritis, septic thrombophlebitis and acute bacterial endocarditis are also relatively common. There are at least three clinical conditions resulting from the toxigenic properties of Staphylococci. The manifestation of these diseases result from the actions of exotoxins as opposed to tissue invasion and bacteremia. These conditions include: Staphylococcal food poisoning, scalded skin syndrome and toxic shock syndrome.
A Blast P search result of publicly available sequence data, using the amino acid sequence of the invention as a query sequence, revealed a Streptococcus mutans homologue, which is a GTP-binding protein (ERA, sp/P42182/BEX_BACSU BEX PROTEIN).
Clearly, there is a need for factors that may be used to screen compounds for antibiotic activity, such as novel ERA of the invention. These factors may also be used to determine their roles in pathogenesis of infection, dysfunction and disease. There is a further need for identification and characterization of such factors and their antagonists and agonists which can play a role in preventing, ameliorating or correcting infections, dysfunctions or diseases.
The polypeptides of the invention have amino acid sequence homology to a known Streptococcus mutans GTP-binding protein ERA protein.
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as novel ERA polypeptides by homology between the amino acid sequence set out in
FIG. 2 and a
known amino acid sequence or sequences of other proteins such as Streptococcus mutans GTP-binding protein ERA protein.
It is a further object of the invention to provide polynucleotides that encode ERA polypeptides, particularly polynucleotides that encode the polypeptide herein designated ERA.
In a particularly preferred embodiment of this aspect of the invention the polynucleotide comprises a region encoding ERA polypeptides comprising the sequence set out in
FIG. 1
[SEQ ID NO: 1], or a variant thereof.
In another particularly preferred embodiment of the invention there is a novel ERA protein from
Staphylococcus aureus
comprising the amino acid sequence of
FIG. 2
[SEQ ID NO: 2], or a variant thereof.
In accordance with this aspect of the invention there is provided an isolated nucleic acid molecule encoding a mature polypeptide expressible by the
Staphylococcus aureus
WCUH 29 strain contained in NCIMB Deposit No. 40771.
In accordance with this aspect of the invention there are provided isolated nucleic acid molecules encoding ERA, particularly
Staphylococcus aureus
ERA, including mRNAs, cDNAs, genomic DNAs. Further embodiments of this aspect of the invention include biologically, diagnostically, prophylactically, clinically or therapeutically useful variants thereof, and compositions comprising the same.
In accordance with another aspect of the invention, there is provided the use of a polynucleotide of the invention for therapeutic or prophylactic purposes, in particular genetic immunization. Among the particularly preferred embodiments of this aspect of the invention are naturally occurring allelic variants of ERA and polypeptides encoded thereby.
In accordance with this aspect of the invention there are provided novel polypeptides of
Staphylococcus aureus
referred to herein as ERA as well as biologically, diagnostically, prophylactically, clinically or therapeutically useful variants thereof, and compositions comprising the same.
Among the particularly preferred embodiments of this aspect of the invention are variants of ERA polypeptide encoded by naturally occurring alleles of the ERA gene.
In a preferred embodiment of this aspect of the invention there are provided methods for producing the aforementioned ERA polypeptides.
In accordance with yet another aspect of the invention, there are provided inhibitors to such polypeptides, useful as antibacterial agents, including, for example, antibodies.
In accordance with certain preferred embodiments of this aspect of the invention, there are provided products, compositions and methods for (i) assessing ERA expression, (ii) treating disease, for example, disease, such as, infections of the upper respiratory tract (e.g., otitis media, bacterial tracheitis, acute epiglottitis, thyroiditis), lower respiratory (e.g., empyema, lung abscess), cardiac (e.g., infective endocarditis), gastrointestinal (e.g., secretory diarrhoea, splenic absces, retroperitoneal abscess), CNS (e.g., cerebral abscess), eye (e.g., blepharitis, conjunctivitis, keratitis, endophthalmitis, preseptal and orbital cellulitis, darcryocystitis), kidney and urinary tract (e.g., epididymitis, intrarenal and perinephric absces, toxic shock syndrome), skin (e.g., impetigo, folliculitis, cutaneous abscesses, cellulitis, wound infection, bacterial myositis) bone and joint (e.g., septic arthritis, osteomyelitis), (iii) assaying genetic variation, (iv) and administering a ERA polypeptide or polynucleotide to an organism to raise an immunological response against a bacteria, especially a
Staphylococcus aureus
bacteria.
In accordance with certain preferred embodiments of this and other aspects of the invention there are provided polynucleotides that hybridize to ERA polynucleotide sequences, particularly under stringent conditions.
In certain preferred embodiments of this aspect of the invention there are provided antibodies against ERA polypeptides.
In accordance with another aspect of the invention, there are provided ERA agonists and antagonists each of which are preferably bacteriostatic or bacteriocidal.
In a further aspect of the invention there are provided compositions comprising a ERA polynucleotide or a ERA polypeptide for administration to a cell or to a multicellular organism.
Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following descriptions and from reading the other parts of the present disclosure.


REFERENCES:
patent: 4431793 (1984-02-01), Riggs
patent: 0 233 715 (1987-08-01), None
Sevier, E., David, G., Martinis, J., Desmond, W., Bartholomew, R. and Wang, R. “Monoclonal Antibodies in Clinical Immunology”Clin. Chem.27/11, 1797-1806 (1981).
Zuber, M., Hoover, T., Powell, B., and Court, D. “Analysis of the mc locus ofCoxiella burnetti” Molecular Microbiology(1994) 14(2), 291-300.
Lerner, C., and Inouye, M. “Pleiotropic changes resulting from depletion of Era, an essential GTP-binding protein inEscherichia coli” Molecular Microbiology(1991) 5(4), 951-957.
Sood, P., Lerner, C., Shimamoto, T., Lu, Q., and Inouye, M. “Characterization of the autophosphorylation of Era, an essentialEscherichia coliGTPase”Molecular Microbiology(1994) 12(2), 201-208.
Yamashita, Y., Takehara, T., and Kuramitsu, K. “Molecular Characterization of aStreptococcus mutansMutant Altered in Environmental Stress Responses”Journal of Bacteriology, Oct. 1993, pp. 6220-6228.
Pillutla, R., Sharer, D., Gulati, P., Wu, E., Yamashita, Y., Lerner, C., Inouye, M., and March, P. “Cross-Species Complementation of the IndespensableEscherichia coliera Gene Highlights Amino Acid Regions Essential for Activity”Journal of Bacteriology, Apr. 1995, pp. 21

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