Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1999-01-28
2001-10-09
Swartz, Rodney P (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S185100, C424S190100, C424S192100, C424S193100, C424S234100, C424S237100, C435S069100, C435S069700, C435S071100, C435S183000, C435S220000, C530S300000, C530S350000, C536S023100, C536S023700
Reexamination Certificate
active
06299883
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 tagF/tarF (CDP-glycerol:poly(glycerophosphate) glycerophospho transferase) family, hereinafter referred to as “tarF”.
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.
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.
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, 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.
A target that would be useful in developing such factors are teichoic acids, which are polymers found in the cell walls of Gram-positive bacteria. Teichoic acids have been shown to be essential for viability and normal morphogenesis of several Gram-positive species. CDP-glycerol:poly(glycerophosphate) glycerophospho transferase is a key enzyme in the wall teichoic acids biosynthetic pathway. The gene is named tarF in
S.aureus,
which makes the ribitol-based polymer, and tagF in
Bacillus subtilis,
which make the glycerol-based polymer. The enzyme adds CDP-activated glycerol in the final step of synthesis of the lipid-linked linkage unit on which the polymer is synthesised. Mutation of this gene has been shown to be lethal in
Bacillus subtilis
and
Staphylococcus aureus
and will prevent the synthesis of wall teichoic acids, which are essential for the viability of Gram-positive cells. Although there are many types of wall teichoic acids in bacteria, the linkage unit structure is conserved in most species tested, and thus inhibition of this enzyme is a valid antibacterial strategy.
The polypeptides of the invention have amino acid sequence homology to a known
Bacillus subtilis
tagF protein. See Briehl et al. 1989. “Mutants of Bacillus subtilis 168 thermosensitive for growth and wall teichoic acid synthesis” J. Gen. Microbiol. 135:1325-1334; GenBank Accession Number X15200.
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as novel tarF 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
Bacillus subtilis
tagF protein.
It is a further object of the invention to provide polynucleotides that encode tarF polypeptides, particularly polynucleotides that encode the polypeptide herein designated tarF.
In a particularly preferred embodiment of the invention the polynucleotide comprises a region encoding tarF 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 tarF 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 tarF, particularly
Staphylococcus aureus
tarF, 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 tarF and polypeptides encoded thereby.
Another aspect of the invention there are provided novel polypeptides of
Staphylococcus aureus
referred to herein as tarF 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 tarF polypeptide encoded by naturally occurring alleles of the tarF gene.
In a preferred embodiment of the invention there are provided methods for producing the aforementioned tarF 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 tarF 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, 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 tarF 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 tarF polynucleotide sequences, particularly under stringent conditions.
In certain preferred embodiments of the invention there are provided antibodies against tarF polypeptides.
In other embodiments of the invention there are provided methods for identifying compounds which bind to or otherwise interact with and inhibit or activate an activity of a polypeptide or polynucleotide of the invention comprising: contacting a polypeptide or polynucleotide of the invention with a compound to be screened under c
Chalker Alison Frances
Fosberry Andrew Peter
Horn Stephanie Van
Ovari Michael
Deibert Thomas S.
Gimmi Edward R.
King William T.
SmithKline Beecham Corporation
Swartz Rodney P
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