Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1999-01-13
2001-04-03
Duffy, Patricia A. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S192100, C424S243100, C514S002600, C530S350000, C530S405000, C530S403000, C530S806000, C530S825000
Reexamination Certificate
active
06210674
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 gre (transcript cleavage factor) family, hereinafter referred to as “greA”.
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 thrombophlebiuis 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.
Transcription of DNA is often arrested at sites in DNA that trap a fraction of elongating RNA polymerase molecules that pass through, resulting in blocked ternary complexes that cannot propagate or dissociate their RNA product. Transcript cleavage factors induce RNA polymerase to cleave the RNA in such complexes at the 3′-end, allowing RNA polymerase to back up and re-attempt to read through the potential trap (Borukhov et al. 1993. Cell 72:459-466). In addition to assuring efficient transcript elongation, transcript cleavage factors increase the fidelity of transcription since misincorporated bases at the 3′-end of the nascent RNA also lead to arrested complexes (Erie et al. Science 262:867-8730. Two transcript cleavage factors, GreA and GreB, have been identified in
E. coli
(Borukhov et al. 1993. Cell 72:459-466). GreA-dependent transcript cleavage usually results in the removal of di- and trinucleotides from the 3′-end of the stalled RNA. GreB-dependent cleavage yields larger oligonucleotides, up to a length of nine nucleotides. Both proteins bind RNA polymerase. Neither the GreA or GreB proteins possess intrinsic nuclease activity rather they stimulate a nuclease activity inherent in RNA polymerase (Orlova et al. 1995. Proc. Natl. Acad. Sci., USA 92:4596-4600). The GreA and GreB proteins are homologous, sharing 38% sequence identity (59% similar). The eukaryotic transcript elongation protein SII is similar to the GreA and GreB proteins in that it stimulates RNA cleavage from the 3′-end of RNA in a stalled complex but does not share significantly sequence homology with the GreA and GreB proteins (Borukhov et al. 1993. Cell 72:459-466).
Clearly, there is a need for factors, such as the novel 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, disfunction 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, disfunctions or diseases.
The polypeptides of the invention have amino acid sequence homology to a known
E. coli
greA protein.
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as novel greA polypeptides 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
E. coli
greA protein.
It is a further object of the invention to provide polynucleotides that encode greA polypeptides, particularly polynucleotides that encode the polypeptide herein designated greA.
In a particularly preferred embodiment of the invention the polynucleotide comprises a region encoding greA polypeptides comprising the sequence set out in Table 1 [SEQ ID NO:1] which includes a full length gene, or a variant thereof.
In another particularly preferred embodiment of the invention there is a novel greA 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 greA, particularly
Staphylococcus aureus
greA, 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 greA and polypeptides encoded thereby.
Another aspect of the invention there are provided novel polypeptides of
Staphylococcus aureus
referred to herein as greA 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 greA polypeptide encoded by naturally occurring alleles of the greA gene.
In a preferred embodiment of the invention there are provided methods for producing the aforementioned greA 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 greA 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., epididyrnitis, 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), assaying genetic variation, and administering a greA 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 greA polynucleotide sequences, particularly under stringent conditions.
In certain preferred embodiments of the invention there are provided antibodies against greA po
Gentry Daniel Robert
Greenwood Rebecca Claire
Deibert Thomas S.
Duffy Patricia A.
Gimmi Edward R.
King William T.
SmithKline Beecham Corporation
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