Blocking expression of virulence factors in S. aureus

Details Blocking expression of virulence factors in S. aureus Blocking expression of virulence factors in S. aureus

1997-05-22

2002-09-10

Graser, Jennifer E. (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

C530S350000, C530S300000, C530S317000, C530S327000, C530S328000, C530S329000, C424S184100, C424S185100, C424S190100, C435S069100, C435S069300

Reexamination Certificate

active

06447786

ABSTRACT:

BACKGROUND OF THE INVENTION
Staphvlococcus aureus
(
S. aureus
) is Gram-positive, aerobic bacterial pathogen, distinguished from other staphylococcal species by the production of the enzyme coagulase.
Sa
is a normal inhabitant of the skin and mucous membranes of man and other animals and under certain circumstances invades the body, causing a wide variety of disease conditions ranging from superficial abscesses (boils and furuncles) to disfiguring and life-threatening deep infections such as endocarditis, pneumonia, osteomyelitis, septic arthritis, meningitis, post-operative wound infections, and septicemia.
Sa
also causes diseases such as toxic shock syndrome.
Like other Gram-positive pathogens,
Sa
causes disease chiefly through the production and secretion of injurious proteins. These injurious extracellular proteins, or virulence factors (VF), include toxins that damage or dissolve host cells, toxins that interfere with the immune system, and enzymes that degrade tissue components such as proteins, nucleic acids, lipids and polysaccharides.
In laboratory cultures, VF are produced and secreted at the end of the standard exponential growth phase, during a segment of the growth cycle known as the post-exponential phase. The production of VF is coordinately regulated and is thought to represent an attempt by the bacteria to generate new sources of nutrition at a time of rapidly diminishing resources. In the infected individual, this may include an attack on the host defenses that have been mobilized to ward off and contain the infection.
Sa
infections are presently treated with antibiotics, which are natural or semisynthetic chemicals that kill or inhibit the growth of bacterial cells. Unfortunately, antibiotics have become less and less effective in treating
Sa
infections due to the acquired resistance of Sa to these antibiotics. Major nosocomial epidemics are now caused worldwide by strains of
Sa
that are resistant to most antibiotics. The antibiotic vancomycin is still effective in treating various strains of
Sa
, although there is a grave danger that those strains will soon acquire resistance to vancomycin from a closely related Gram-positive pathogen,
Enterococcus faecalis.
Since there is little reason to expect the introduction of major new classes of antibiotics, there is an urgent need to develop new methods to control
Sa
infections, such as interference with the expression of VF. If the bacteria could be disarmed, it is believed that host defenses would do the rest.
In
S. aureus
, expression of virulence factors is controlled by a global regulator known as agr (Peng, H., et al.
J. Bacteriol
. 179: 4365-4372 (1988); Regassa, L. B., et al.
Infect. Immun
. 60: 3381-3383 (1992)). Agr is a genetic locus that contains several genes. Two of these, agrA and agrC, are thought to constitute a signal transduction (STR) pathway that responds to one or more external signalling molecules by activating the transcription of a third gene, agr-rnaIII (Kornblum, J., et al., in Molecular Biology of the Staphylococci, R. P. Novick, ed. (VCH Publishers, New York, 1990); Bourret, R. B., et al.
Annu. Rev. Biochem
. 60: 401-441 (1991)). The primary transcript of aqr-rnaIII, known as RNAIII, induces transcription of the 20 or more independent genes encoding virulence factors, thereby resulting in the synthesis of VF (Novick, R. P., et al.
EMBO Journal
12(10): 3967-3975 (1993)).
It has been shown that laboratory-generated mutant strains of
Sa
, unable to express VF, exhibit greatly reduced virulence (Foster, et al.
Molecular Biology of the Staphylococci
, Editor: R. P. Novick, VCH Publishers, New York, pp. 403-420 (1990)). Interference with activation of the agr system would therefore afford a simple means of blocking the expression of VF, and thus interfere with the infective process. Raychoudhury, S. et al.
PNAS
90:965-969 (1993) recently described the identification of synthetic chemical compounds that block the expression of alginate, a VF for the cystic fibrosis pathogen,
Pseudomonas aeruginosa
. It has not been shown, however, whether these chemicals would have any effect on
Sa
, or offer any potential clinical utility.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery of peptides which interfere with the activation of rnaIII transcription and thus prevent expression of VF. Prevention of the expression of VF by
S. aureus
using peptides which inhibit activation of rnaIII transcription are expected to prevent or treat diseases caused by Staphylococcal infections. Finally, the peptides of the present invention, in addition to treating or preventing diseases or infection caused by
S. aureus
, also can be used in vitro for preventing colonization of
S. aureus
.


REFERENCES:
patent: WO9610579 (1996-04-01), None
Soe et al. J. Virol. 1987, 61(12): 3968-3976.*
Fukuhara et al. 1993, Plant Molec. Biol. 21: 1121-1130.*
Moriyama et al. 1995, Mol Gen. Geret. 248:364-369.*
Vandenesch et al. 1993, FEMS Microbiol. Lett. 111:115-122.*
Janzon et al, 1989, Mol.Gen. Genet. 219:480-485.*
Novick et al. 1995, Mol. Gen. Genet. 248: 446-458.*
Naomi Balaban, et al., entitled “Autocrine Regulation Of Toxin Synthesis By Staphylococcus Aureus,”Proc. Natl. Acad. Sci., vol. 92, pp. 1619-1623, Feb. 1995.
R.P. Novick, et al., entitled “The agr P2 Operon: An Autocatalytic Sensory Transduction System In Staphylococcus Aureus,”Molecular&General Genetics (1995)248: 446-458.
Richard P. Novick, et al., entitled “Synthesis Of Staphylococcal Virulence Factors Is Controlled By A Regulatory RNA Molecule,”The EMBO Journal, vol. 12, No. 10, pp. 3967-3975, 1993.
Eva Morfeldt, et al., entitled “Activation Of Alpha-Toxin Translation In Staphylococcus Aureus By the Trans-Encoded Antisense RNA, RNAIII,”The EMBO Journal, vol. 14, No. 18, pp. 4569-4577, 1995.
Naomi Balaban, et al., entitled Translation of RNAIII, The Staphylococcus Aureus AGR Regulatory RNA Molecule, Can Be Activated By A 3′-End Deletion,FEMS Microbiology Letters, 133 (1995) 155-161.
Ambrose L. Cheung, et al., entitled “Cloning And Sequencing Of sarA Of Staphylococcus Aureus, A Gene Required For The Expression of agr”,Journal of Bacteriology, Jul. 1994, p. 4168-4172, vol. 176, No. 13.
Francois Vandenesch, et al., entitled “A Temporal Signal, Independent Of agr, Is Required For hla But Not spa Transcription In Staphylococcus Aureus”,Journal of Bacteriology, Oct. 1991, p. 6313-6320, vol. 173, No. 20.
Ji, et al., entitled “Cell Density Control Of Staphylococcal Virulence Mediated By An Octapeptide Pheromone”, Proceedings of The National Academy of Sciences, USA, Dec. 1995, vol. 92, No. 6, pp. 12055-12059.

Affiliated with

Also associated with

Rating

Blocking expression of virulence factors in S. aureus does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Blocking expression of virulence factors in S. aureus, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Blocking expression of virulence factors in S. aureus will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2837197