Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
2000-12-19
2002-02-19
Duffy, Patricia A. (Department: 1645)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C424S185100, C424S190100, C424S192100, C424S234100, C424S244100
Reexamination Certificate
active
06348579
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 ftsl family, hereinafter referred to as “FtsL”.
BACKGROUND OF THE INVENTION
The Streptococci make up a medically important genera of microbes known to cause several types of disease in humans, including, for example, otitis media, conjunctivitis, pneumonia, bacteremia, meningitis, sinusitis, pleural empyema and endocarditis, and most particularly meningitis, such as for example infection of cerebrospinal fluid. Since its isolation more than 100 years ago,
Streptococcus pneumoniae
has been one of the more intensively studied microbes. For example, much of our early understanding that DNA is, in fact, the genetic material was predicated on the work of Griffith and of Avery, Macleod and McCarty using this microbe. Despite the vast amount of research with
S. pneumoniae,
many questions concerning the virulence of this microbe remain. It is particularly preferred to employ Streptococcal genes and gene products as targets for the development of antibiotics.
The frequency of
Streptococcus pneumoniae
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
Streptococcus pneumoniae
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.
FtsL is a membrane bound protein involved in bacterial cell division. ftsL is essential for cell growth and division. An ftsL null mutation results in inhibition of cell division, the formation of long, non-septate filaments, and ultimately cessation of growth and lysis (Guzman L-M., Barondess, J. J., and Beckwith, J. (1992) J. Bacteriol 174: 7716-7728).
In
Escherichia coli
the ftsL gene is located immediately upstream of ftsI which codes for Penicillin-binding protein 3, a membrane protein specifically required during septation (Ishino, F., & Matsuhashi, M. (1981) Biochem. Biophys. Res. Commun. 101: 905-911). FtsL is also a cytoplasmic membrane protein with a cytoplasmic N-terminus, a membrane-spanning segment, and a periplasmic carboxy terminus.
Although there are many examples of cell division proteins in
E. coli
their precise functions are mostly unknown. However it is likely that membrane proteins involved in cell division will have a major role in the regulation of cell division and in septum initiation.
FtsL homologues have been reported in Haemophilus influenzae (Fleischmann, R. et al (1995) Science 269: 496-512) and
Bacillus subtilis
(Daniel, R. A., Williams, A. M., Errington, J. (1995) Genbank Accession Z68230).
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
Bacillus subtilis
ftsl protein.
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as novel FtsL 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
ftsl protein.
It is a further object of the invention to provide polynucleotides that encode FtsL polypeptides, particularly polynucleotides that encode the polypeptide herein designated FtsL.
In a particularly preferred embodiment of the invention the polynucleotide comprises a region encoding FtsL 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 FtsL protein from
Streptococcus pneumoniae
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
Streptococcus pneumoniae
0100993 strain contained in the deposited strain.
A further aspect of the invention there are provided isolated nucleic acid molecules encoding FtsL, particularly
Streptococcus pneumoniae
FtsL, 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 FtsL and polypeptides encoded thereby.
Another aspect of the invention there are provided novel polypeptides of
Streptococcus pneumoniae
referred to herein as FtsL 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 FtsL polypeptide encoded by naturally occurring alleles of the FtsL gene.
In a preferred embodiment of the invention there are provided methods for producing the aforementioned FtsL 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 FtsL expression, treating disease, for example, otitis media, conjunctivitis, pneumonia, bacteremia, meningitis, sinusitis, pleural empyema and endocarditis, and most particularly meningitis, such as for example infection of cerebrospinal fluid, assaying genetic variation, and administering a FtsL polypeptide or polynucleotide to an organism to raise an immunological response against a bacteria, especially a
Streptococcus pneumoniae
bacteria.
In accordance with certain preferred embodiments of this and other aspects of the invention there are provided polynucleotides that hybridize to FtsL polynucleotide sequences, particularly under stringent conditions.
In certain preferred embodiments of the invention there are provided antibodies against FtsL 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 conditions to permit binding to or other interaction between the compound and the polypeptide or polynucleotide to assess the binding to or other interaction with the compound, such binding or interaction being associated with a second component capable of providing a detectable signal in response to the binding or interaction of the polypeptide or polynucleotide with the compound; and determining whether the compound binds to or otherwise interacts with and activates or inhibits an activity of the polypeptide or polynucleotide by detecting the presence or absence of a signal generated from the binding or interaction of
Diebert Thomas S.
Duffy Patricia A.
Gimmi Edward R.
King William T.
SmithKline Beecham Corporation
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