Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-03-19
2001-05-29
Clark, Deborah J. R. (Department: 1633)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S252300, C435S320100, C435S325000, C536S023100, C536S023500
Reexamination Certificate
active
06238885
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 polynucleotides and polypeptides of the histidine kinase family, as well as their variants, herein referred to as “histidine kinase,” “histidine kinase polynucleotide(s),” and “histidine kinase polypeptide(s)” as the case may be.
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 thromboplebitis 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 that are resistant to some or all of the standard antibiotics. This phenomenon has created an unmet medical need and demand for new anti-microbial agents, vaccines, drug screening methods, and diagnostic tests for this organism.
Moreover, the drug discovery process is currently undergoing a fundamental revolution as it embraces “functional genomics,” that is, high throughput genome- or gene-based biology. This approach is rapidly superseding earlier approaches based on “positional cloning” and other methods. Functional genomics relies heavily on the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available as well as from other sources. There is a continuing and significant need to identify and characterize further genes and other polynucleotides sequences and their related polypeptides, as targets for drug discovery.
Clearly, there exists a need for polynucleotides and polypeptides, such as the histidine kinase embodiments of the invention, That have a present benefit of, among other things, being useful to screen compounds for antimicrobial 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.
SUMMARY OF THE INVENTION
The present invention relates to histidine kinase, in particular histidine kinase polypeptides and histidine kinase polynucleotides, recombinant materials and methods for their production. In another aspect, the invention relates to methods for using such polypeptides and polynucleotides, including treatment of microbial diseases, amongst others. In a further aspect, the invention relates to methods for identifying agonists and antagonists using the materials provided by the invention, and for treating microbial infections and conditions associated with such infections with the identified agonist or antagonist compounds. In a still further aspect, the invention relates to diagnostic assays for detecting diseases associated with microbial infections and conditions associated with such infections, such as assays for detecting histidine kinase expression or activity.
Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following descriptions and from reading the other parts of the present disclosure.
DESCRIPTION OF THE INVENTION
The invention relates to histidine kinase polypeptides and polynucleotides as described in greater detail below. In particular, the invention relates to polypeptides and polynucleotides of a histidine kinase of
Staphylococcus aureus,
that is related by amino acid sequence homology to ResE protein from B.subtilis polypeptide. The invention relates especially to histidine kinase having a nucleotide and amino acid sequences set out in Table 1 as SEQ ID NO:1 and SEQ ID NO:2 respectively. Note that sequences recited in the Sequence Listing below as “DNA” represent an exemplification of the invention, since those of ordinary skill will recognize that such sequences can be usefully employed in polynucleotides in general, including ribopolynucleotides.
TABLE 1
histidine kinase Polynucleotide and Polypeptide Sequences
(A)
Staphylococcus aureus
histidine kinase polynucleotide sequence [SEQ ID NO:1]
5′- 1
AGAAAAGTTA AATCGTGTGT CTAGCGAAGC TGCGCATATG ATTCAAACAG
51
TCTGGGGCGT TGGGTATAAA TTTGAGGTTA AATCTAATGA TGAGCCGGCT
101
AAATAGTGTC GTAATTAAAC TGTGGTTAAC TATTATTTTA ATAGTGACGA
151
CAGTTTTAAT TTTATTAAGT ATTGCTTTAA TTACCTTTAT GCAATACTAT
201
TTCACACAAG AAACCGAAAA TGCCATAAGA GAAGATGCTA GACGTATAAG
251
TTCACTGGTC GAACAATCAC ATAATAAAGA AGAAGCAATA AAATATAGTC
301
AAACATTAAT TGAAAATCCT GGTGGGTTGA TGATTATAAA TAATAAACAT
351
CGTCAATCAA CGGCTTCACT TTCTAATATT AAAAAGCAAA TGTTGAATGA
401
AGTAGTCAAC AACGACCATT TTGACGATGT GTTTGATAAA GGTAAATCTG
451
TTACTCGAAA TGTAACGATT AAAGAAAAGG GTTCATCTCA AACATATATT
501
TTGTTAGGCT ATCCAACAAA AGCACAGAAG AATAGTCATA GCAAATATAG
551
TGGAGTCTTT ATATATAAAG ACTTGAAATC AATCGAAGAT ACAAATAATG
601
CTATTACGAT TATCACTATA ATTACGGCTG TTATTTTCTT AACAATTACA
651
ACAGTCTTTG CGTTTTTCTT ATCGTCAAGA ATTACAAAAC CTTTAAGACG
701
TTTAAGAGAC CAAGCTACAC GTGTATCTGA AGGGGATTAC TCTTATAAAC
751
CTTCTGTCAC AACGAAAGAT GAAATTGGTC AATTATCGCA GGCATTTAAT
801
CAGATGAGTA CAGAAATCGA AGAGCATGTC GACGCATTAT CCACATCTAA
851
AAATATTAGA GACAGCTTAA TTAACTCTAT GGTAGAAGGT GTCCTAGGTA
901
TTAATGAGAG TCGACAAATT ATCTTATCTA ATAAGATGGC GAATGATATT
951
ATGGACAATA TTGATGAAGA TGCTAAAGCT TTCTTATTAA GACAAATTGA
1001
AGATACTTTT AAATCAAAAC AAACGGAAAT GCGTGATTTA GAAATGAATG
1051
CACGATTCTT TGTTGTGACC ACAAGCTATA TCGATAAGAT TGAACAGGGA
1101
GGTAAAAGTG GTGTTGTTGT GACAGTTCGT GATATGACTA ATGAGCACAA
1151
TCTAGATCAA ATGAAGAAAG ATTTCATTGC TAATGTATCA CATGAATTAC
1201
GAACACCTAT ATCATTACTA CAAGGTTATA CTGAATCAAT TGTAGATGGT
1251
ATTGTTACAG AACCGGATGA AATAAAAGAA TCGCTCGCCG TTGTCCTTGA
1301
TGAATCGAAA CGTTTAAATC GATTAGTTAA TGAATTGTTA AATGTCGCAC
1351
GCATGGATGC TGAAGGGTTA TCCGTAAATA AAGAAGTTCA GCCTATTGCA
1401
GCGTTACTAG ATAAGATGAA AATTAAGTAT CGCCAACAAG CTGATGATTT
1451
AGGTCTAAAT ATGACTTTTA ATTATTGTAA GAAGCGTGTT TGGAGTTATG
1501
ATATGGATCG CATGGACCAA GTACTAACGA ACTTAATTGA TAATGCATCA
1551
CGTTATACGA AACCTGGAGA TGAAATTGCA ATTACTTGTG ATGAAAATGA
1601
AAGCGAAGAT ATTTTATACA TTAAAGATAC AGGCACAGGC ATTGCACCAG
1651
AACATTTACA ACAAGTATTT GATCGTTTTT ATAAAGTTGA TGCAGCGAGA
1701
ACGCGAGGTA AACAAGGTAC CGGTTTAGGT TTGTTCATTT GTAAAATGAT
1751
TATCGAAGAG CATGGTGGTT CCATTGATGT TAAAAGCGAA TTAGGAAAAG
1801
GCACAACATT TATTATTAAA CTACCAAAAC CAGAATAAAA CTGAATATAG
1851
TTATTTAAGA ACGCATGTTA TTGATTAGAG ACTCTAATTT ATAGCATGCG
1901
TTTTTTGATT GATGTCGAAA GTTTTGTAAG TGGATTAGGA TTAGGGTTTT
1951
TGCGAATATC AACTATTAAA TATATTACTA ATTTATATAA AAATATAAAG
2001
TTTGATAAAG TTATTTATTT GATTATAAAA ATAGGGTAAA ATATAGATAT
2051
ATTGTAATAA TTAAATTATT CGAGGTGTCA TATGAAAAAA TTCATTGGAT
2101
CAGTTTTAGC TACGACATTA ATTTTAGGGG GATGTTCCAT GATGGAAAAT
2151
GAATCAAGTA AAGACACGAA TACAGAAACA AAATCAGTAC CAGAAGAAAT
2201
GGAAGCTTCA AAATATGTAG GACAAGGCTT CCAACCACCT GCAG -3′
(B)
Staphylococcus aureus
histidine kinase polypeptide sequ
Clark Deborah J. R.
Deibert Thomas S.
Gimmi Edward R.
King William T.
SmithKline Beecham Corporation
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