Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-11
2003-12-30
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06670374
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a process for reducing the manifestation of disease by enteric bacterial pathogens in animals using swainsonine compounds.
2. Description of the Prior Art
A number of diseases of humans and other animals are associated with the production of toxins by enteric bacteria.
Escherichia coli
O157:H7 and other shiga toxin-producing strains have recently gained widespread public attention in the United States due to their recently recognized association with two serious extraintestinal diseases in humans, hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Worldwide, enterohemorrhagic
E. coli
, including
E. coli
O157:H7 and other shiga toxin-producing
E. coli
, are an increasingly important health problem in humans and other animals. First identified as a cause of human illness in early 1982 following two outbreaks of food-related hemorrhagic colitis in Oregon and Michigan (M. A. Karmali, 1989, Infection by Verocytotoxin-Producing
Escherichia coli
, Clin. Microbiol. Rev., 2:15-38; and L. W. Riley, et al., 1983, Hemorrhagic colitis associated with a rare
Escherichia coli
serotype, New Eng. J. Med., 308: 681-685), the reported incidence of disease associated with enterohemorrhagic
E. coli
has risen steadily, with outbreaks occurring in the United States, Canada, and Europe.
SUMMARY OF THE INVENTION
We have now discovered a method for treating infections in animals which are caused by toxin-producing enteric bacterial pathogens, including Shigella species, enterohemorrhagic
E. coli
, and enterotoxigenic
E. coli
. Receptors expressed by animal cells which typically recognize these bacterial toxins may be modified by administration of a swainsonine compound to the animal, thereby effectively inhibiting toxin binding to the cells.
In accordance with this discovery, it is an object of this invention to provide a method for treating infections caused by toxin-producing enteric bacterial pathogens.
Another object of this invention is to provide a method for treating infections of Shigella species, enterohemorrhagic
E. coli
, and enterotoxigenic
E. coli.
Yet another object of the invention is to provide a method for treating infections caused by toxin-producing enteric bacterial pathogens which does not target the bacteria per se, such that the development of bacterial resistance is irrelevant.
Other objects and advantages of this invention will become readily apparent from the ensuing description.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides a method for preventing or mitigating one or more conditions in an animal which are mediated by the toxins elicited by enteric bacterial pathogens. As described in greater detail hereinbelow, in accordance with this invention, the administration of one or more swainsonine compounds to a susceptible animal effects the modification of cell surface receptors for the toxins, thereby interfering with the binding of the toxins to the cells and reducing or preventing cell cytotoxicity. The method is effective for treating animals against infection by a number of toxin-producing enteric pathogens, including but not limited to enterotoxigenic
E. coli
(ETEC), and particularly shiga toxin-producing Shigella species and enterohemorrhagic
E. coli
such as
E. coli
O157:H7. As described by Nataro and Kaper (Diarrheagic
Escherichia coli
, Clinical Microbiology Reviews, 1998, vol. 11, no. 1, pp. 142-201, the contents of which are incorporated by reference herein) and as used herein, enterotoxigenic
E. coli
refers to
E. coli
strains that elaborate at least one of two defined groups heat labile or heat stable enterotoxins (LT or ST, respectively). In contrast, enterohemorrhagic
E. coli
refers to
E. coli
strains that produce one or more shiga toxins (also referred to as shiga-like toxins, SLTs, or verotoxins) which comprise an enzymatically active A subunit and a multimeric cell receptor binding B subunit. Infections caused by common serotypes of enterohemorrhagic and enterotoxigenic
E. coli
which may be treated in accordance with this invention are provided in Table 1 hereinbelow.
TABLE 1
Pathogenic
E. coli
Serotypes (Group and Associated Serotypes)
Enterotoxigenic (ETEC)
O6:H16; O8:NM; O8:H9; O11:H27; O15:H11; O20:NM; O25:NM;
O25:H42; O27:H7; O27:H20; O63:H12; O78:H11; O78:H12;
O85:H7; O114:H21; O115:H21; O126:H9; O128ac:H7;
O128ac:H12; O128ac:H21; O148:H28; O149:H4; O159:H4;
O159:H20; O166:H27; and O167:H5
Enterohemorrhagic (EHEC)
O1:NM; O2:H5; O2:H7; O4:NM; O4:H10; O5:NM; O5:H16;
06:H1; O18:NM; O18:H7; O25:NM; O26:NM; O26:H11;
O26:H32; O8:H21; O39:H4; O45:H2; O50:H7; O55:H7;
055:H10; O82:H8; O84:H2; O91:NM; O91:H21; O103:H2;
O111:NM; O111:H8; O111:H30; O111:H34; O113:H7;
O113:H21; O114:H48; O115:H10; O117:H4; O118:H12;
O118:H30; O121:NM; O121:H19; O125:NM; O125:H8; O126:NM;
O126:H8; O128:NM; O128:H2; O128:H8; O128:H12; O128:H25;
O145:NM; O125:H25; O146:H21; O153:H25; O157:NM;
O157:H7; O163:H19; O165:NM; O165:19; and O165:H25
Many Shigella species produce shiga toxin and thus the method of the invention may be used for the treatment of a variety of Shigella species. Due to the incidence and severity of infections therewith, the method is particularly suited for the treatment of infections caused by
S. dysenteriae, S. sonnei, S. boydii
, and
S. flexneri.
Without wishing to be bound by theory, the swainsonine compounds are believed to inhibit Golgi mannosidase II activity, thereby interfering with the expression of fully functional cell surface receptors for the bacterial enterotoxins. Thus, the cells of the treated animals exhibit significantly reduced binding of the enterotoxin relative to untreated or normal cells. In the case of infections by Shigella species or enterohemorrhagic
E. coli
, it is believed that protection may be the result of the modification of either or both of the glycolipid receptors globotriaosylceramide (GB
3
or GB
4
) on the epithelial or other cell surfaces, or a second, low affinity shiga toxin binding site. The mechanism of this modification may be an interruption in the translocation process of the receptor from the site of synthesis to the outer cell membrane surface, or the synthesis of a receptor having significantly reduced toxin binding affinity. Animal host cells expressing cell surface receptors which may be effectively modified include but are not limited to epithelial (endothelial) cells of the gastrointestinal tract, glomerular cells of the kidney, endothelial cells of the mesenteric vasculature, and cerebral endothelial cells.
A variety of swainsonine compounds are suitable for use in the method of this invention, including swainsonine, derivatives of swainsonine, and salts of swainsonine or its derivatives. A number of such swainsonine compounds have been described in the prior art and may be used herein. By way of example, suitable swainsonine compounds include but are not limited to those disclosed by Tropper et al. (U.S. Pat. No. 6,051,711), Shah et al. (U.S. Pat. No. 6,048,870), Carver et al. (U.S. Pat. No. 5,962,467), Pearson et al. (U.S. Pat. No. 6,262,065), and Dime (U.S. Pat. No. 5,466,809), the contents of each of which are incorporated by reference herein.
As used herein, the term swainsonine compounds is therefore defined to include swainsonine, its salts, swainsonine derivatives, and their salts. Swainsonine derivatives are further defined as biologically effective molecules which retain the same indolizidine alkaloid base molecule as swainsonine wherein one or more of the 1-3 or 5-9 carbons contain additional or different (i.e., substituted) chemical moieties which are not normally part of swainsonine. The term “biologically effective” is also defined herein as effective for the inhibition of activity of &agr;-D-mannosidases, specifically Golgi mannosidase II, and thereby effective for inhibiting the expression of fully functional enterotoxin receptors on the cell surfaces of the subject animal and consequently inhibiting the binding of the enterotoxins to the
Anderson Robin C.
Droleskey Robert E.
Nisbet David J.
Deck Randall E.
Fado John D.
The United States of America as represented by the Secretary of
Weddington Kevin E.
LandOfFree
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