Lead substances and their use as therapeutics

Details Lead substances and their use as therapeutics Lead substances and their use as therapeutics

1998-12-24

2003-12-09

Smith, Lynette R. F. (Department: 1645)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

6 to 7 amino acid residues in defined sequence

C530S300000, C530S317000

Reexamination Certificate

active

06660835

ABSTRACT:

The invention relates to peptides and their use in treatment of diseases caused by Staphylococci.
Staphylococci are amongst the most important pathogens of nosocomial infections. Nosocomial infections are often communicated by banal germs and take place simultaneously with medical care and nursing. They are often due to deficiencies in hygiene, lack of room in hospital and uncritical use of antibiotics. As a result of relative fast development of antibiotic resistance the conventional treatment of Staphylococcus infections by application of antibiotics is often without success and the spreading of pathogens is hardly to stop. That is why it is necessary to find new ways to treat such kind of infections.
The genus Staphylococcus comprises several species relevant| to medicine, such as
S. aureus
and
S. epidermidis
, which are cause of various symptoms. These pathogens excrete toxins, enzymes or polysaccharides being crucial for the clinical picture. Many of these virulence factors are controlled by the so-called agr system (acessory gene regulator system) of the germs.
The invention has the object to provide new possibilities for treating diseases or disorders caused by Staphylococci, in particular by providing compounds, which are able to interfere with the regulation of the agr system in order to block the formation of different virulence factors.
This problem is solved by the peptides according the present invention. The nucleic acid sequence encoding for the peptides and the nucleic acid sequence of the agr system of Staphylococcus epidermidis and vectors comprising parts of said sequences are claimed herein. Appropriate hosts for the inventive vectors are shown herein. Pharmaceutical compositions and the use of the inventive chemical compounds in treating diseases and disorders are shown herein. The wording of all claims is hereby made to the content of the specification by reference.
As mentioned above many virulence factors, e.g. exoproteins, of Staphylococcus species, including alpha-toxin, beta-toxin, delta-toxin, serin protease, DNase, fibrinolysin, enterotoxin B, and toxic shock syndrome toxin-1, are controlled by the agr system. This is especially known for
S. aureus
(Novick et al., 1993).
The agr locus of
S. aureus
, about 3.5 kb in size, comprises the agrA, agrC, agrD, and agrB genes, which are cotranscribed (forming the mRNA RNAII), and the gene for a regulatory RNA molecule, RNAIII; the RNAIII DNA region also encodes the gene for the delta-toxin (hid). RNAIII controls the expression of target genes by an unknown mechanism. The agr genes are transcribed from the P2 promoter, and the RNAIII molecule is synthesized from the P3 promoter (Novick et al., 1995). The roles of AgrB and AgrD have recently become more clear. A small peptide is excised from the AgrD protein, modified, and secreted as the agr pheromone peptide into the surrounding medium. This peptide represents the autoinductive signal of the agr system; the pheromone activates the AgrC/AgrA two-component regulatory system that in turn activates transcription of the agrBDCA and RNAIII genes (Ji et al., 1997; Ji et al., 1995).
The peptides according to the invention e.g. block the action of the pheromone of
S. aureus
and therefore prevent the forming of virulence factors.


REFERENCES:
Mahony et al. (PNAS vol. 92, pp. 6474-6478, 1995).*
Fleischmann et al. (Science Vol 269 pp. 496-512, 1995).*
Van Wamel et al. (FEMS Microbiology Letters vol. 163 pp. 1-9, 1998).*
Novick et al., EMBO Journal, vol. 12, No. 10, pp. 3967-3975 (1993).
Novick et al., Mol. Gen. Genet., 248: 446-458 (1995).
Michael Otto et al., FEBS Letters, 424, pp. 89-94 (1998).
Mayville et al., Proc. Natl. Acad. Sci. USA, 96: 1218-1223 (1999).

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