Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-10-08
2002-02-19
Minnifield, Nita (Department: 1645)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023700, C536S023100, C536S023200, C435S069100, C435S173300, C435S320100, C435S071100, C435S252300, C435S007100, C435S007920
Reexamination Certificate
active
06348584
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 polynucleotides and polypeptides of the fibronectin binding protein family, hereinafter referred to as “Fibronectin Binding Protein”.
BACKGROUND OF THE INVENTION
It is particularly preferred to employ Staphiylococcal 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.
The frequency of
Staphylococcus aureus
infections has risen dramatically in the past 20 years. This has been attributed to the emergence of multiply antibiotic resistant strains and an increasing population of people with weakened immune systems. It is no longer uncommon to isolate
Staphylococcus aureus
strains which are resistant to some or all of the standard antibiotics. This has created a demand for both new anti-microbial agents and diagnostic tests for this organism.
The cell surface proteins fibronectin binding protein, fibrinogen binding protein, collagen binding protein and protein A of
Staphylococcus aureus
have all been identified as having peptidoglycan spanning regions rich in proline and glycine residues, N-terminal to the LPXTG motif characteristic of surface proteins in grain-positive bacteria. See Surface-associated proteins of
Staphylococcus aureus
: Their possible roles in virulence. Foster, T. J. and McDevitt, D. [1994] FEMS Microbiology Letters 118, 199-206.
Different approaches have been put forward to address such proteins from
Staphylococcus aureus
as antibacterial targets, e.g. fibronectin bindinig proteins (EP0294349, EP0397633, WO94/18327), fibrinogen binding protein (WO94/06830), collagen binding protein (WO92/07002) and bone sialoprotein binding protein (WO94/13310). The binding proteins or binding fragments thereof are used as antibacterial agents to block binding of the organism to host tissue, as vaccines to raise antibodies to the organism in the host animal or as antigens to raise therapeutic antibodies which can be used to block binding of the organism to host tissue.
Clearly, there is a need for factors, such as the compounds of the invention, that have a present benefit of being useful to screen compounds for antibiotic activity. Such factors are also useful to determine their role in pathogenesis of infection, dysfunction and disease. There is also a 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
S. aureus
fibronectin binding protein A protein.
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as Fibronectin Bindinig Protein polypeptides of the invention by homology between the amino acid sequence set out in Table 1 [SEQ ID NO: 2] and a known amino acid sequence or sequences of other proteins such as
S. aureus
fibronectin binding protein A protein.
It is a further object of the invention to provide polynucleotides that encode Fibronectin Binding Protein polypeptides, particularly polynucleotides that encode the polypeptide herein designated Fibronectin Binding Protein.
In a particularly preferred embodiment of the invention the polynucleotide comprises a region encoding Fibronectin Binding Protein polypeptides comprising the sequence set out in Table 1 [SEQ ID NO:1], or a variant thereof.
In another particularly preferred embodiment of the invention there is a Fibronectin Binding Protein protein from
Staphylococcus aureus
comprising the amino acid sequence of Table 1 [SEQ ID NO:2], or a variant thereof.
In accordance with another 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 the deposited strain.
A further aspect of the invention there are provided isolated nucleic acid molecules encoding Fibronectin Binding Protein, particularly
Staphylococcus aureas
Fibronectin Bindinig Protein, including mRNAs, cDNAs, genomic DNAs. Further embodiments 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 the invention are naturally occurring allelic variants of Fibronectin Binding Protein and polypeptides encoded thereby.
Another aspect of the invention there are provided polypeptides of
Staphylococcus aureus
referred to herein as Fibronectin Binding Protein as well as biologically, diagnostically, prophylactically, clinically or therapeutically useful variants thereof, and compositions comprising the same.
Among the particularly preferred embodiments of the invention are variants of Fibronectin Bindinig Protein polypeptide encoded by naturally occurring alleles of the Fibronectin Binding Protein gene.
In a preferred embodiment of the invention there are provided methods for producing the aforementioned Fibronectin Binding Protein 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 the invention, there are provided products, compositions and methods for assessing Fibronectin Binding Protein expression, 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, intrarenial 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), assaying genetic variation, and administering a Fibronectin Binding Protein 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 tile invention there are provided polynucleotides that hybridize to Fibronectin Binding Protein polynucleotide sequences, particularly under stringent conditions.
In certain preferred embodiments of the invention there are provided antibodies against Fibronectin Binding Protein polypeptides.
In other embodiments of the invention there are provided methods for identifying compounds which bind to or otherw
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