Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-04-02
2001-09-18
Davenport, Avis M. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C530S300000, C530S329000, C424S185100, C424S520000
Reexamination Certificate
active
06291431
ABSTRACT:
BACKGROUND OF THE INVENTION
Staphylococcus aureus
causes diseases chiefly through the production of virulence factors such as hemolysins, enterotoxins and toxic shock syndrome toxin. The synthesis of virulence factors in
S. aureus
is controlled by a regulatory RNA molecule, RNAIII (Novick, et al.,
EMBO J.
12, 3967 (1993), Balaban et al.,
FEMS Microbiol. Letts.
133, 155 (1995), Moerfeldt et al.,
EMBO J.
14, 4569 (1995)), encoded by the agr locus. The rnaiii gene of the agr locus is transcribed in culture only from the midexponential phase of growth, and is autoinduced by the protein RNAIII activating protein (RAP)(Balaban et al.,
Proc. Natl. Acad. Sci. U.S.A.
92, 1619 (1995)). RAP is continuously secreted by the bacteria and only activates RNAIII at a concentration threshold (ibid).
Antibodies to RAP block the activation of rnaiii in vitro. A peptide, termed RNAIII inhibiting peptide (RIP) is produced by a nonpathogenic strain of
S. aureus
mutated by nitrosoguanidine (ibid). RIP competes with RAP for the activation of RNAIII, and thus inhibits toxin production by
S. aureus
(ibid).
Staphylococcus aureus
causes diseases ranging from minor skin infections to life-threatening deep infections such as pneumonia, endocarditis, meningitis, post-operative wound infections, septicemia, and toxic shock syndrome (Silverstein et al., in
Microbiology,
Davis et al., eds. (Lippincott, Philadelphia, 1990), pp. 485-506). Hospitalized patients are at particular risk, with over 500,000 nosocomial infections per year (Panlilio, et al.,
Inf. Contr. and Hosp. Epidem.
13, 582 (1992)). The emergence of drug resistance has made many of the available antimicrobial agents ineffective. Therefore, alternative methods for the prevention and treatment of bacterial infections in general and
S. aureus
infections in particular are eagerly sought. The instant invention addresses this need and others.
SUMMARY OF THE INVENTION
One aspect of the invention is a composition comprising a polypeptide comprising an amino acid sequence comprising the general formula Y(K or S) PXTNF (SEQ ID NOS:1 and 2), where X is C, W, or I. Pharmaceutical compositions are also provided in some embodiments.
A further aspect of the invention is a composition of claim
1
, wherein the polypeptide comprises an amino acid sequence comprising the general formula IKKY(K or S) PXTNF (SEQ ID NOS:3 and 4), where X is C, W, or I.
A further aspect of the invention is a method for treating a host for a staphylococcal infection, wherein the composition of claim
1
is administered to the host. In some embodiments the host is a human patient. In further embodiments the host is an animal, such as but not limited to an experimental animal.
A further aspect of the invention is a method for treating a host for a staphylococcal infection, wherein an antagonist of the RAP receptor is administered to the host. In some embodiments the host is a human patient. In further embodiments the host is an animal, such as but not limited to an experimental animal. In some embodiments the antagonist is a polypeptide, a peptidomimetic, or an antibody.
A further aspect of the invention is a nucleic acid molecule encoding a polypeptide of the invention. The nucleic acid molecule can be RNA or DNA or an antisense nucleic acid molecule. In an embodiment, the nucleic acid molecule comprises the nucleotide sequence TAT TCG CCG TGG ACC AAT TTT (SEQ ID NO:5).
REFERENCES:
patent: WO96/10579 (1996-04-01), None
patent: WO97/44349 (1997-11-01), None
Ji, et al. “Cell Density Control ofStaphylococcusVirulence Mediated by an Octapeptide Pheromone,”Proc. Natl. Acad. Sci. USA(1995) 92:12055-12059.
Ji, et al. “Bacterial Interference Caused by Autoinducing Peptide Variants”Science(1997) 276:2027-2030.
Mayville, et al. “Structure-Activity Analysis of Synthetic Autoinducing Thiolactone Peptides formStaphylococcus AureusResponsible for Virulence,”Proc. Natl. Acad. Sci. USA(1999) 96:1218-1223.
Novick, et al., “Virulence Gene Regulation by Peptides inStaphylococciand other Gram-positive Bacteria,”Curr. Opin. in Microbiol.(1999) 2:40-45.
Balaban et al,PNAS,(1995), vol. 92 No. 5, pp. 1619-1623.*
Balaban et al.,Science,1998, vol. 280, No. 5362 pp. 438-440.*
Balaban et al. “Autocrine regulation of toxin synthesis byStaphylococcus aureas” Proc. Natl. Acad. Sci. USA (1995) 92:1619-1623.
Balaban et al., “Translation of RNAIII, theStahylococcus aureasagr regulatory RNA molecule, can be activated by a 3′-end deletion” FEMS Microbiol. Letters (1995) 133:155-161.
Morfeldt et al., “Activation of alpha-toxin translation inStaphylococcus aureusby the trans-encoded antisense RNA, RNAIII” EMBO Journal (1995) 14(18):4569-4577.
Novick et al., “Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule” EMBO Journal (1993) 12(120):3967-3975.
Panlilio et al., “Methicillin-resistantStaphylococcus aureusin U.S. hospitals, 1875-1991” Infect. Control Hosp. Epidemiol. (1992) 13:582-586.
Silverstein et al., “Host Defense against bacterial and fungal infections” Microbiology, Fourth Edition, J.B. Lippincott Company, Philadelphia, B.D. Davis et al., Eds., Chapter 21, pp. 485-505.
Balaban Naomi
Larrick James W.
Wright Susan C.
Bozicevic Field & Francis LLP
Davenport Avis M.
Francis Carol L.
Panorama Research
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