3-dehydroquinate synthase

Details 3-dehydroquinate synthase 3-dehydroquinate synthase

1999-09-17

2001-05-15

Cochrane Carlson, Karen (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

57, C530S350000, C530S300000

Reexamination Certificate

active

06232292

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 aromatic acid biosynthetic gene family, hereinafter referred to as “3-DEHYDROQUINATE SYNTHASE”.
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.
Aromatic amino acids are synthesized in bacteria from the common precursor, chorismic acid. Chorismic acid is itself synthesized in bacteria from phosphoenol pyruvate and erythrose-4-phosphate via 3-dehydroquinate which is made by a synthase encoded by the aroB gene. The gene in
Escherichia coli
has been cloned (see Millar G, Coggins J R FEBS Lett, 200(1):11-17 (1986)).
Substantial effort has been invested this century in the successful discovery and development of antibacterials. Paradoxically, although antibacterials are devised to eradicate infection in mammals, we know almost nothing of the physiology of bacterial pathogens in infective situations in the host. Using sequences from the
Staphylococcus aureus
chromosome, we have developed an RT-PCR based procedure which allows us to identify those bacterial genes transcribed at any stage of infection and also from different niches of infection. The derivation of such information is a critical first step in understanding the global response of the bacterial gene complement to the host environment. From the knowledge of bacterial genes both of known and unknown function which are widely transcribed in the host it is possible to attempt to ascertain by database searching those which are present only in the eubacteria. Further prioritization of such genes by consideration of the likely role of their products towards the maintenance of infection and the facility of setting up a screen for inhibitors of the biochemical function indicated by their homology to characterised genes allows the compilation of a shortlist for gene essentiality studies using genetic deletion or controlled regulation techniques. The proteins expressed by genes shown to be necessary for growth in vitro or in pathogenesis in animal models provide novel targets for antibacterial screening to find agents which are broadly inhibitory towards pathogenesis. This invention provides
S. aureus
WCUH 29 polynucleotides which are transcribed in infected tissue, in particular in both acute and chronic infections.
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.
The polypeptides of the invention have amino acid sequence homology to a known 3-dehydroxyquinate synthase (EC 4.6.1.3) protein, identified as AROB_BACSU in the Swiss Prot database. See Swiss Prot, Accession Number P31102.
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as novel 3-DEHYDROQUINATE SYNTHASE 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 AROB_BACSU 3-DEHYDROQUINATE SYNTHASE protein.
It is a further object of the invention to provide polynucleotides that encode 3-DEHYDROQUINATE SYNTHASE polypeptides, particularly polynucleotides that encode the polypeptide herein designated 3-DEHYDROQUINATE SYNTHASE.
In a particularly preferred embodiment of the invention the polynucleotide comprises a region encoding 3-DEHYDROQUINATE SYNTHASE 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 3-DEHYDROQUINATE SYNTHASE 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 3-DEHYDROQUINATE SYNTHASE, particularly
Staphylococcus aureus
3-DEHYDROQUINATE SYNTHASE, 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 3-DEHYDROQUINATE SYNTHASE and polypeptides encoded thereby.
Another aspect of the invention there are provided novel polypeptides of
Staphylococcus aureus
referred to herein as 3-DEHYDROQUINATE SYNTHASE 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 3-DEHYDROQUINATE SYNTHASE polypeptide encoded by naturally occurring alleles of the 3-DEHYDROQUINATE SYNTHASE gene.
In a preferred embodiment of the invention there are provided methods for producing the aforementioned 3-DEHYDROQUINATE SYNTHASE 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 3-DEHYDROQUINATE SYNTHASE 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 cellul

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