Histidine kinase

Details Histidine kinase Histidine kinase

2000-08-18

2003-04-15

Monshipouri, M. (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Transferase other than ribonuclease

C435S252300, C435S320100, C435S006120, C530S350000

Reexamination Certificate

active

06548281

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, the invention relates to novel polynucleotides and polypeptides of the Histidine Kinase family, hereinafter referred to as “Histidine Kinase”.
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.
Staphylococcus 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 few decades. 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 phenomenon has created a demand for both new anti-microbial agents, vaccines, and diagnostic tests for this organism.
Many two component signal transduction systems (TCSTS) have been identified in bacteria (Stock, J. B., Ninfa, A. J. & Stock, A. M.(1989) Microbiol. Rev. 53, 450-490). These are involved in the bacterium's ability to monitor its surroundings and adapt to changes in its environment. Several of these bacterial TCSTS are involved in virulence and bacterial pathogenesis within the host.
Histidine kinases are components of the TCSTS which autophosphorylate at a histidine residue. The phosphate group is then transferred to the cognate response regulator. The histidine kinases have five short conserved amino acid sequences (Stock, J. B., Ninfa, A. J. & Stock, A. M.(1989) Microbiol. Rev. 53, 450-490, Swanson, R. V., Alex, L. A. & Simon, M. I.(1994) TIBS 19 485-491). These are the histidine residue, which is phosphorylated, followed after approximately 100 residues by a conserved asparagine residue. After another 15 to 45 residues a DXGXG motif is found, followed by a FXXF motif after another 10-20 residues. 10-20 residues further on another glycine motif, GXG is found. The two glycine motifs are thought to be involved in nucleotide binding. This family of histidine kinases includes KinA protein from
Lactococcus lactis cremoris
(O'Connell-Motherway, M., Fitzgerald, G. F. & van Sinderen, D. (1997) Appl. Environ. Microbiol. 63 2454-2459).
Response regulators are components of the TCSTS. These proteins are phosphorylated from histidine kinases and in turn once phosphorylated affect the response, often through a DNA binding domain becoming activated. The response regulators are characterized by a conserved N-terminal domain of approximately 100 amino acids. The N-terminal domains of response regulators as well as retaining five functionally important residues, corresponding to the residues D12, D13, D57, T87, K109 in CheY (Matsumura, P., Rydel, J. J., Linzmeier, R. & Vacante, D. (1984) J. Bacteriol. 160, 36-41), have conserved structural features (Volz, K. (1993) Biochemistry 32, 11741-11753). The 3-dimensional structures of CheY from
Salmonella typhimurium
(Stock, A. M., Mottonen, J. M., Stock, J. B. & Schutt, ,C. E. (1989)
Nature
, 337, 745-749) and
Escherichia coli
(Volz, K. & Matsumura, P. (1991)
J. Biol. Chem
. 266, 15511-15519) and the N-terminal domain of nitrogen regulatory protein C from
S.typhimurium
(Volkman, B. F., Nohaile, M. J., Amy, N. K., Kustu, S. & Wemmer, D. E. (1995) Biochemistry, 34 1413-1424), are available, as well as the secondary structure of SpoOF from
Bacillus subtilis
(Feher, V. A., Zapf, J. W., Hoch, J. A., Dahlquist, F. W., Whiteley, J. M. & Cavanagh, J. (1995) Protein Science, 4, 1801-1814). These structures have a (a/b)
5
fold. Several structural residues are conserved between different response regulator sequences, specifically hydrophobic residues within the &bgr;-sheet hydrophobic core and sites from the a-helices.
Among the processes regulated by TCSTS are production of virulence factors, motility, antibiotic resistance and cell replication. Inhibitors of TCSTS proteins would prevent the bacterium from establishing and maintaining infection of the host by preventing it from producing the necessary factors for pathogenesis and thereby have utility in anti-bacterial therapy.
Clearly, there exists a need for factors, such as the Histidine Kinase embodiments 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 to find ways to prevent, ameliorate or correct such infection, dysfunction and disease.
Certain of the polypeptides of the invention possess amino acid sequence homology to a known KinA from
Lactococcus lactis cremoris
protein. (O'Connell-Motherway, M., Fitzgerald, G. F. & van Sinderen, D. (1997) Appl. Environ. Microbiol. 63 2454-2459; U81166 from Genbank.)
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as novel Histidine Kinase 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 KinA from
Lactococcus lactis cremoris
protein.
It is a further object of the invention to provide polynucleotides that encode Histidine Kinase polypeptides, particularly polynucleotides that encode the polypeptide herein designated Histidine Kinase.
In a particularly preferred embodiment of the invention, the polynucleotide comprises a region encoding Histidine Kinase polypeptides comprising a 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 Histidine Kinase protein from
Staphylococcus aureus
comprising the amino acid sequence of Table 1 [SEQ ID NO:2], or a variant thereof.
As a further aspect of the invention, there are provided isolated nucleic acid molecules encoding Histidine Kinase, particularly
Staphylococcus aureus
Histidine Kinase, 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 Histidine Kinase and polypeptides encoded thereby.
In another aspect of the invention, there are provided novel polypeptides of
Staphylococcus aureus
referred to herein as Histidine Kinase 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 Histidine Kinase polypeptide encoded by naturally occurring alleles of the Histidine Kinase gene.
In a preferred em

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