Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-06-30
2003-06-24
Marschel, Ardin H. (Department: 1631)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S006120, C435S243000, C435S320100, C435S325000, C536S024300, C536S024320
Reexamination Certificate
active
06583275
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to isolated nucleic acids and polypeptides derived from
Enterococcus faecium
that are useful as molecular targets for diagnostics, prophylaxis, and treatment of pathological conditions, as well as materials and methods for the diagnosis, prevention, and amelioration of pathological conditions resulting from bacterial infection.
BRIEF DESCRIPTION OF THE SEQUENCE LISTING
Incorporated herein by reference in its entirety is a Sequence Listing, comprising SEQ ID NO: 1 to SEQ ID NO: 7310. The Sequence Listing is contained on a CD-ROM, three copies of which are filed, the Sequence Listing being in a computer-readable ASCII file named “GTC-012 sub seq.pto”, created on Jul. 13, 2001 and of 14,112 kilobytes in size, in Windows NT 4.0 format.
BACKGROUND OF THE INVENTION
Enterococcus faecium
is a Gram-positive, nonmotile, nonpigmented cocci, that is widely distributed in nature, animals, and humans. Enterococci are part of the normal gastrointestinal and genital tract flora, and among the 17 known species,
E. faecium
is one of the most prominent in humans, with the highest levels of multidrug resistance (A. Kaufhold and R. Klein (1995) Zentralblatt fuer Bakteriologie 282 507). Pathogenic
E. faecium
infections include urinary tract infections (UTI), bacteremia, endocarditis, and wound and abdominal-pelvic infections.
Vancomycin resistant Enterococci (VRE) have emerged in the midst of high level resistance to penicillin and aminoglycosides (Centers for Disease Control and Prevention, 1993
MMWR
42:597; and S. Handwerger et al., 1993,
Clin Infect Dis
16:750). VRE are characterized by resistance to virtually all available antibiotics, including vancomycin which is considered the “last resort” antibiotic effective against gram-positive bacteria. Treatment options for physicians are limited, with the latest strategy being combinations of antimicrobials or the use of new unproven compounds (R. C. Moellering, Jr.,1991,
J Antimicrob Chemother
28:1; and M. K. Hayden et al., 1994,
Antimicrob Agents Chemother
38:1225; and N. Mobarakai et al., 1994,
J Antimicrob Chemother
33:319). From 1989 through 1993, the percentage of nosocomial (hospital incurred) infections by VRE increased from 0.3% to 7.9% (Centers for Disease Control and Prevention, 1993,
MMWR
42:597). There was a 34-fold increase in Intensive Care Unit (ICU) patients, and an increasing trend among non-ICU patients (Centers for Disease Control and Prevention, 1993,
MMWR
42:597). These numbers may not be an accurate reflection of the actual total, as clinical identification of vancomycin resistance is not consistently detected, especially in the VanB phenotype which confers moderate resistance (F. C. Tenover, 1993,
J Clin Microbiol
31:1695; and D F Sahm, 1990,
Antimicrob Agents Chemother
34: 1846; and R J Zabransky, 1994
Microbiol Infect Dis
20:113). Patients can be colonized and carry VRE without symptoms, with chief areas of colonization being anus, axilla, stool, perineal, umbilicus, wounds, foley catheters, and colostomy sites.
Epidemiology of
E. faecium
is not completely understood, but it is thought that most infections and colonizations are a result of the patient's endogenous flora (B E Murray, 1990,
Clin Microbiol Rev
3:46). Recent evidence suggests that
E. faecium
can be spread by direct contact with other infected patients, indirect transmission from hospital personnel (J M Boyce et al., 1 994,
J Clin Microbiol
32:1148-; and E. Rhineheart et al., 1990,
N Engl J Med
323:1814), or from contaminated hospital surfaces and equipment (L V Karanfil et al., 1992,
Infect Control Hosp Epidemiol
13:195; and J M Boyce et al., 1994,
J Clin Microbiol
32:1148; and L L Livornese Jr., 1992,
Ann Intern Med
117:112). Increased risk for the critically ill, those with underlying disease or immunosuppression i.e. ICU, oncology, and transplant patients, cardio-thoracic/intraabdominal surgical patients and those with urinary or central venous catheters, has been demonstrated. In addition, risk for;
E. faecium
infection increases for patients with long hospital stays or previous multiantimicrobial or vancomycin treatments (J. M. Boyce et al., 1994,
J Clin Microbiol
32:1148; Boyle, J. F. et al., 1993,
J Clin Microbiol
31:1280; L V Karanfil et al., 1992,
Infect Control Hosp Epidemiol
13:195; S. Handwerger et al., 1993,
Clin Infect Dis
16:750; Montecalvo, M. A. et al., 1994,
Antimicrob Agents Chemother
38:1363-1367).
Additional concern stems from the ability of the
E. faecium
plasmid borne VanA gene, which confers high level vancomycin resistance, to transfer in vitro to several gram positive microorganisms such as
Staphylococcus aureus
(Leclercq, R. et al., 1989,
Antimicrob Agents Chemother
33:10; and Noble, W. C., et al., 1992,
FEMS Microbiology Letters
72:195). To date, no clinical isolates of
S. aureus
or
S. epidermidis
have shown vancomycin resistance conferred by plasmid transfer, but clinically isolated strains of
S. haemolyticus
have shown vancomycin resistance (Degner, J. E. et al., 1994,
J Clin Microbiol
32:2260; and Veach, L. A. et al., 1990,
J Clin Microbiol
28:2064).
These concerns point to the need for diagnostic tools and therapeutics aimed at proper identification of
E. Faecium
strains and the eradication of virulence. The design of vaccines that will limit the spread of infection and halt transfer of resistance factors is very desirable.
SUMMARY OF THE INVENTION
The present invention fulfills the need for diagnostic tools and therapeutics by providing bacterial-specific compositions and methods for detecting, treating, and preventing bacterial infection, in particular
E. Faecium
infection.
The present invention encompasses isolated polypeptides and nucleic acids derived from
E. faecium
that are useful as reagents for diagnosis of bacterial infection, components of effective antibacterial vaccines, and/or as targets for antibacterial drugs, including anti-
E. faecium
drugs. The nucleic acids and peptides of the present invention also have utility for diagnostics and therapeutics for
E. faecium
and other Enterococcus species. They can also be used to detect the presence of
E. faecium
and other Enterococcus species in a sample; and in screening compounds for the, ability to interfere with the
E. faecium
life cycle or to inhibit
E. faecium
infection. More specifically, this invention features compositions of nucleic acids corresponding to entire coding sequences of
E. faecium
proteins, including surface or secreted proteins or parts thereof, nucleic acids capable of binding mRNA from
E. faecium
proteins to block protein translation, and methods for producing
E. faecium
proteins or parts thereof using peptide synthesis and recombinant DNA techniques. This invention also features antibodies and nucleic acids useful as probes to detect
E. faecium
infection. In addition, vaccine compositions and methods for the protection or treatment of infection by
E. faecium
are within the scope of this invention.
The nucleotide sequences provided in SEQ ID NO: 1-SEQ ID NO: 3654, a fragment thereof, or a nucleotide sequence at least 99.5% identical to a sequence contained within SEQ ID NO: 1-SEQ ID NO: 3654 may be “provided” in a variety of medias to facilitate use thereof. As used herein, “provided” refers to a manufacture, other than an isolated nucleic acid molecule, which contains a nucleotide sequence of the present invention, i.e., the nucleotide sequence provided in SEQ ID NO: 1-SEQ ID NO: 3654, a fragment thereof, or a nucleotide sequence at least 99.5% identical to a sequence contained within SEQ ID NO: 1-SEQ ID NO: 3654. Uses for and methods for providing nucleotide sequences in a variety of media is well known in the art (see e.g., EPO Publication No. EP 0 756 006)
In one application of this embodiment, a nucleotide sequence of the present invention can be recorded on computer readable media. As used herein, “computer readable media” refers to any media which can be read and accessed directly by a computer. S
Bush David
Doucette-Stamm Lynn A.
Genome Therapeutics Corporation
Genome Therapeutics Corporation
Marschel Ardin H.
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