MX2007009196A - 18-membered macrocycles and analogs thereof. - Google Patents

Abstract

The present invention relates generally to the 18-membered macrocyclic antimicrobial agents called Tiacumicins, specifically, OPT-80 (which is composed almost entirely of the R-Tiacumicin B), pharmaceutical compositions comprising OPT-80, and methods using OPT-80. In particular, this compound is a potent drug for the treatment of bacterial infections, specifically <i>C. difficile </i>infections.

Description

MACROCYCLIC COMPONENTS OF 18 MEMBERS AND ANALOGUES OF THE SAME FIELD OF THE INVENTION The present invention relates in general to 18-member macrocyclic antimicrobial agents called Tiacumicins, specifically, R-Tiacumicin B or Tiacumicin B and their related compounds. Particularly, substantially pure R-Tiacumicin B, as a potent antibiotic agent for the treatment of bacterial infections, specifically GI infections caused by the toxin produced by the strains of Clostridium difficile (C. difficile), Staphylococcus aureus (S. aureus) including the Methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium perfringens (C. perfringens). BACKGROUND OF THE INVENTION Macrocycles are an important therapeutic class of antibiotics. These compounds are frequently produced as a family of closely related biogenetic congeners. Tiacumicins are a series of 18-member macrocyclic antibiotics in which the macrocyclic ring is glycosidically bound to one or two sugars. A seven-carbon sugar is esterified in several positions with small fatty acids. The other sugar, when present, is esterified with an acid isomer benzoic, energetic acid completely substituted. (Journal of Liquid Chromatography, 1988, 11: 191-201). Tiacumicins are a family of related compounds that contain the 18 member ring shown in Formula I below.

Formula I Currently, several distinct Tiacumicins have been identified and six of these (Tiacumicin AF) are defined by their particular pattern of substituents R1, R2, and R3 (U.S. Patent No. 4,918,174, J. Antibiotics, 1987, 40: 575-588), as shown in Table 1. Table 1. Substituents present in Tiacumicins AF Tiacumicins A-F have been characterized in a spectroscopic manner and by other physical methods. The chemical structures of the Tiacumicins are based on the spectroscopy: UV-vis, IR and NMR of XH and 13C, see for example J. Antibiotics, 1987, 40: 575-588. The inspection in Table 1 reveals that certain members of the family are structurally related isomers and / or differ by the presence or absence of certain radicals. Others differ in the nature of their ester groups. Tiacumicins are produced by bacteria, including the Dactylosporangium Aurantiacum subspecies Hamdenensis, which can be obtained from the Center's ARS Patent Collection of Northern Regional Research, United States Department of Agriculture, 1815 North University Street, Peoria, IL 61604, accession number NRRL 18085. Characteristics of strain AB 718C-41 are given in J. Antibiotics, 1987, 40: 567-574 and in US Patent No. 4, 918, 174. Diarrhea associated with C. difficile (CDAD) is a disease characterized by severe and painful diarrhea. C. difficile is responsible for approximately 20% of the cases of diarrhea associated with the antibiotic (ADA) and the majority of cases of colitis associated with the antibiotic (AAC). These diseases are typically caused by the toxin produced by strains of C. difficile, S. aureus including methicillin-resistant S. aureus (RSA) and Clostridium perfringens (C. perfringens). The ADA represents a significant economic burden on the health system that is conservatively estimated at $ 3-6 billion per year in excess costs in hospitals in the United States alone. Enterococci resistant to Vancomycin, for which intestinal colonization provides a constant reservoir for infection, has also emerged as a major nosocomial pathogen associated with increased costs and mortality in health care. VRE may appear as coinfection in patients infected with C. difficile, or more commonly cause infection in certain high-risk patients such as hematology and oncology patients, patients in intensive care units and patients receiving solid organ transplants. Staphylococci resistant to methicillin, such as MRSA, are increasing in predominance in both hospitals and community settings. Staphylococci are found on the skin and within the digestive and respiratory tracts but can infect open wounds and burns and can progress to a serious systemic infection. The emergence of multidrug-resistant staphylococci, especially in the hospital where antibiotic use is frequent and selective pressure by drug-resistant organisms is high, has shown a challenge in treating these patients. The presence of MRSA in the skin of patients and health care workers promotes the transmission of organisms resistant to multiple drugs. Similar diseases, including but not limited to clostridial enterocolitis, neonatal diarrhea, antibiotic-associated enterocolitis, sporadic enterocolitis, and nosocomial enterocolitis are also significant problems in some animal species.

ADA is a significant problem in hospitals and long-term care facilities and in the community. C. difficile is the main cause of ADA in the hospital environment, considering approximately 20% of cases of ADA and the majority of cases of colitis associated with the antibiotic (AAC). The increasing incidence of diarrhea associated with Clostridium difficile (CDAD) has been attributed to the frequent prescription of broad-spectrum antibiotics to hospitalized patients. The most serious form of the disease is pseudomembranous colitis (PMC), which is manifested histologically by colitis with mucosal plaques, and clinically by severe diarrhea, abdominal cramps, and systemic toxicity. The ratio of total CDAD mortality is low, but it is much higher in patients who develop severe colitis or systemic toxicity. A recent study has shown that even when death is not directly attributable to C. difficile, the mortality rate in patients with CDAD with respect to corresponding case controls is much higher. Diarrhea and colitis are caused by the development of one or more C.difficile toxins. The organism proliferates in the colon in patients who have been given broad spectrum antibiotics or, less commonly, chemotherapy against cancer. CDAD is diagnosed in approximately 20% of hospitalized patients who develop diarrhea after treatment with such agents. Currently there are two dominant therapies for CDAD: vancomycin and metronidazole. Vancomycin is not recommended for first-line treatment of CDAD primarily because it is the only active antibiotic against some life-threatening, multi-drug resistant bacteria. Therefore, in an effort to minimize the occurrence of vancomycin-resistant Enterococcus (VRE) or vancomycin-resistant S.aureus (VRSA), the medical community discourages the use of this drug except when absolutely necessary. Metronidazole is recommended as initial therapy without concern for the promotion and selection of vancomycin-resistant intestinal flora, especially enterococci. Despite reports that the frequency of resistance of C. difficile can be > 6% in some countries, metronidazole remains almost as effective as vancomycin, is considerably less expensive, and can be used orally or intravenously. Metronidazole is associated with significant adverse effects including nausea, neuropathy, leukopenia, seizures, and a toxic reaction to alcohol. Also, it is not safe to use in children or pregnant women. Recurrence Clinical symptoms occur in up to 20% of cases after treatment with vancomycin or metronidazole. Therapy with metronidazole has been reported as an important risk factor for VRE colonization and infection. The current treatment regimen against gastrointestinal infections, for example, diarrhea associated with Clostridium difficile (CDAD) is quite uncomfortable, requiring up to 500 mg four times a day for 10 to 14 days. Thus, there is a need for better treatment for cases of CDAD as well as for cases of other diarrheas associated with the antibiotic (ADA) and colitis associated with the antibiotic (AAC). Tiacumicins, specifically Tiacumicin B, show activity against a variety of bacterial pathogens and particularly against C. difficile, a Gram-positive bacterium (Antimicrob Agents Chemother, 1991, 1108-1111). C. difficile is a spore-forming, anaerobic bacterium that causes an infection of the intestines. Diarrhea is the most common symptom but abdominal pain and fever can also occur. C. difficile is a major causative agent of colitis (inflammation of the colon) and diarrhea that may occur after the antibiotic is admitted. This bacterium is acquired mainly in hospitals and chronic care facilities. Because Tiacumicin B shows promising activity against C. difficile, is expected to be useful in the treatment of bacterial infections, especially those of the gastrointestinal tract, in mammals. Examples of such treatments include but are not limited to the treatment of colitis and the treatment of irritable bowel syndrome. Tiacumicins can also find use for the treatment of gastrointestinal cancers. Tiacumicin antibiotics are described in U.S. Patent No. 4,918,174 (issued April 17, 1990), J. Antibiotics 1987, 40: 575-588, J. Antibiotics 1987, 40: 567-574, J. Liquid Chromatography 1988 , 11: 191-201, Antimicrobial Agents and Chemotherapy 1991, 35: 1108-1111, U.S. Patent No. 5,583,115 (issued December 10, 1996), and U.S. Patent No. 5,767,096 (issued June 16, 1998). ), which are incorporated herein by reference. Related compounds are Lipiarmycin antibiotics (cf, J. Chem. Soc. Perkin Trans. I, 1987, 1353-1359 and J. Antibiotics 1988, 41: 308-315) and Clostomycin antibiotics (J. Antibiotics 1986, 39 : 1407-1412), which are incorporated herein by reference. BRIEF DESCRIPTION OF THE INVENTION The present invention relates to new pharmaceutical compositions containing R-Tiacumicins, specifically optically pure R-Tiacumicin B, and to the use of these new compositions together with existing drugs to treat infections caused by gram-positive anaerobic organisms. One embodiment of the present invention is directed towards the discovery that the chiral center in C-19 of Tiacumicin B has a large effect on biological activity. It has now been discovered that a substantially pure preparation of R-Tiacumicin B of higher activity, which has an R-hydroxy group at C-19 has surprisingly very low MIC values than the optically pure S-isomer of Tiacumicin B and of other compounds related to Tiacumicin B. In another embodiment of the present invention, substantially pure R-Tiacumicin B has an unusually long post-antibiotic activity (PAE). This invention includes the composition of new antibiotic agents, which contain substantially pure R-Tiacumicins, by submerged aerobic fermentation of the microorganism Oactylosporangium aurantiacum subspecies hamdenensis. The production method is covered by WO 2004/014295 A2, which is hereby incorporated by reference. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the chemical structure of R-Tiacumicin B by the Oak Ridge Thermal Ellipsoid Graphing Program (ORTEP). DETAILED DESCRIPTION OF THE INVENTION Definitions The term "condition associated with the antibiotic" refers to a condition that results when the antibiotic therapy alters the balance of the microbial flora of the intestine, allowing pathogenic organisms such as the enterotoxin that produce the C-strains. difficile, S. aureus and C. perfringens flourish. These organisms can cause diarrhea, pseudomembranous colitis, and colitis and are manifested by diarrhea, urgency, abdominal cramps, tenesmus, and fever among other symptoms. Diarrhea, when severe, causes dehydration and the medical complications associated with dehydration. The term "asymmetrically substituted" refers to a molecular structure in which an atom having four tetrahedral valencies is attached to four different atoms or groups. The most common cases involve the carbon atom. In such cases, two optical isomers (enantiomers D- and L- or enantiomers R- and S-) per carbon atom result, which are mirror images not superimposable on each other. Many compounds have more than one carbon asymmetric. This gives rise to the possibility of many optical isomers, being the number determined by the formula 2n, where n is the number of asymmetric carbons. The term "broth" as used herein refers to the fluid culture medium as obtained during or after fermentation. The broth comprises a mixture of water, the desired antibiotics, unused nutrients, living or dead organisms, metabolic products, and the adsorbent with or without the product fixed by adsorption. The term "C-19 ketone" refers to a compound related to Tiacumicin B shown below in formula II: Formula II The term "diastereomers" refers to stereoisomers that are not mirror images of one another. The term "enantiomer" refers to a non-superimposable mirror image of itself. An enantiomer of a Optically active isomer rotates the polarized light from the plane in a direction equal but opposite to that of the original isomer. A solution of equal parts of an optically active isomer and its enantiomer is known as a racemic solution and has a net rotation of polarized light from the plane of zero. The enantiomers will have the prefixes opposite one another: D- will be L- or R- will be S-. Often only one enantiomer is active in a biological system, because most biological reactions are enzymatic and enzymes can bind only one of the enantiomers. The term "excipient" refers to an inert substance added to a pharmacological composition to further facilitate the administration of a compound. Examples of excipients include but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. The term "halogen" includes F, Cl, Br and I. The term "isomeric mixture" means a mixture of two or more different chemical species in a configurational manner having the same chemical formula. An isomeric mixture is a genus comprising individual isomeric species. Examples of isomeric mixtures include stereoisomers (enantiomers and diastereomers), regioisomers, which may result, for example, from a pericyclic reaction. The Compounds of the present invention comprise asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms can give rise to mixtures of stereoisomers on an asymmetrically substituted carbon atom or a single stereoisomer. Consequently, racemic mixtures, mixtures of diastereomers, in addition to the diastereomers alone of the compounds of the invention are included in the present invention. The term "Lipiarmycin A4" refers to a compound related to Tiacumicin B shown below in formula III: Formula III The term "lower alkyl", alone or in combination, refers to an optionally substituted straight chain or an optionally substituted branched chain having from 1 to about 8 carbons (eg, Ci, C2, C3, C4, C5, C6, C7, C8,), more preferably from 1 to 4 carbons (for example, Ci, C2, C3, C /). Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. A "lower alkyl" is generally a shorter alkyl, for example, one containing from 1 to about 4 carbon atoms (eg, Ci, C2, C3, C4,). The term "macrocycles" refers to organic molecules with long ring structures that generally contain more than 10 atoms. The term "18-member macrocycles" refers to organic molecules with ring structures that contain 18 atoms. The term "with ring members" may comprise any cyclic structure, including carbocycles and heterocycles such as those described above. The term "in the form of limbs" refers to denoting the number of atoms in the skeleton that make up the ring. Thus, for example, pyridine, pyran and thiopyran are 6-membered rings and pyrrole, furan, and thiophene are 5-membered rings. The term "MIC" or "minimum inhibitory concentration" refers to the lowest concentration of an antibiotic that is necessary to inhibit the growth of a bacterial isolate in vitro A common method for determining the MIC of an antibiotic is to prepare several tubes containing various dilutions of the antibiotic, which are then inoculated with the bacterial isolate of interest. The MIC of an antibiotic can be determined from the tube with the lowest concentration that shows no turbidity (no growth). The term "MIC50" refers to the lowest concentration of the antibiotic required to inhibit the growth of 50% of the bacterial strains tested within a given bacterial species. The term "MIC90" refers to the lowest concentration of the antibiotic required to inhibit the growth of 90% of the bacterial strains tested within a given bacterial species. The term "OPT-80" refers to a preparation that contains approximately 70-100%, preferably, 90% (with respect to the total antibiotic substance, by HPLC assay) of optically pure R-Tiacumicin B (which has a R-hydroxy group at C-19, see formula IV). The remaining portions consist essentially of small amounts of compounds related to Tiacumicin B (including, but not limited to Lipiarmycin A4 and Cetone C-19). Preparations of this type are described in detail in the PCT application PCT / US03 / 21977, which has a number international publication WO 2004/014295 A2 and preparations which are incorporated herein by reference. However, for rigorous exclusive use in non-humans, "OPT-80" containing less than 70% optically pure R-Tiacumicin B (with respect to the total antibiotic substance, by HPLC assay) can be used. The term "ORTEP" refers to the Oak Ridge Thermal Ellipsoid Graphing computer program, written in Fortran, to draw illustrations of the crystal structure. Illustrations type spheres and rods of a suitable quality for the publication are produced either with spheres or ellipsoids of thermal movement probability, derived from parameters of the anisotropic temperature factor, in the atomic sites. The program also produces stereoscopic pairs of illustrations that aid in the visualization of complex arrays of atoms and their correlated thermal motion patterns. The term "PAE" or "post-antibiotic effect" refers to a well-established pharmacodynamic parameter that reflects the persistent suppression of bacterial growth after exposure to the antibiotic. The term "patient" refers to a human being or an animal in need of medical treatment. For the purposes of this invention, human patients they are typically institutionalized in a primary care facility such as a hospital or hospice for the elderly. However, the treatment of a disease associated with the use of antibiotics or chemotherapies for cancer or antiviral therapies can occur on a non-patent basis, after the release of a primary care facility, or can be prescribed by a physician for home care, without association with a primary care facility. Animals in need of medical treatment are typically found in the care of a veterinarian. The term "pharmaceutically acceptable carrier" refers to a carrier or diluent that is pharmaceutically acceptable. The term "pharmaceutically acceptable salts" refers to those derived from pharmaceutically acceptable organic and inorganic bases. Salts derived from appropriate bases include alkali metals (eg, sodium or potassium), alkaline earth metals (eg, magnesium), ammonium and salts of N (Ci-C) alkyl +, and the like. Illustrative examples of some of these include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like. The term "pharmaceutical composition" refers to a mixture of one or more of the Tiacumicins described herein, or to physiologically acceptable salts thereof, with others chemical components, such as physiologically acceptable carriers and / or excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. The term "physiologically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not negate the activity and biological properties of the compound administered. The term "pseudomembranous colitis" or "enteritis" refers to the formation of pseudomembranous material (i.e., material composed of fibrin, mucosa, necrotic epithelial cells and leukocytes) due to the inflammation of the mucous membrane of both the small and large intestines. The terms of configuration "R" and "S", as used herein, are as defined by the IUPAC Recommendations 1974 by Section E, Fundamental Stereochemistry, Puré Appl. Chern. (1976) 45, 13-30. Chiral molecules can be named based on the atomic numbers of the atoms or the groups of atoms, the ligands that are attached to the chiral center. Ligands are given a priority (the higher the atomic number the higher the priority) and if priorities increase in a clockwise direction, they are said to be R. Otherwise, if HE it gives them priority in a counter-clockwise direction they are said to be S-. The term "R-Tiacumicin B" refers to the optically pure (R) isomer of Tiacumicin B with a (R) -hydroxy group at C-19, as shown below in Formula IV: OH Formula IV The term "S-Tiacumicin B" refers to the optically pure isomer (S) of Tiacumicin B with a (S) -hydroxy group at C-19, as shown below in Formula V: OH Formula V The term "stereoisomers" refers to compounds whose molecules have the same number and type of atoms and the same atomic arrangement, but differ in their spatial arrangement. The term "sugar" generally refers to mono-, di- or oligosaccharides. A saccharide can be substituted, for example, glucosamine, galactosamine, acetylglucose, acetylgalactose, N-acetylglucosamine, N-acetylgalactosamine, galactosyl-N-acetylglucosamine, N-acetylneuraminic acid (sialic acid), etc., in addition to sulphated sugars and phosphorylated For the purposes of this definition, saccharides are found in their pyranose or furanose form. The term "Tiacumicin" as used herein refers to a family of compounds which comprise the 18 member macrocycle shown in Formula I: Formula I The term "Tiacumicin B" as used herein refers to the 18 member macrocyclic shown below in Formula VI: Formula VI The term "yield" as used herein refers to an amount of crude Tiacumicin reconstituted in methanol at the same volume as in the original fermentation broth. The yield is determined using standard HPLC techniques. The yield is reported in units of mg / L. This invention includes the composition of new antibiotic agents, Tiacumicins, by submerged aerobic fermentation of the microorganism Dactylosporangium aurantiacum subspecie hamdenensi. The production of the method is covered by WO 2004/014295 A2. The present invention relates to novel antibacterial compositions containing R-Tiacumicins, specifically R-Tiacumicin B (which has an R-hydroxy at C-19) and to the use of these new compositions in combination with existing drugs to treat infections caused by anaerobic gram-positive organisms. The present invention is further related to the new preparation OPT-80 which contains 70-100%, preferably 90% (with respect to the total antibiotic substance, by HPLC assay) of R-Tiacumicin B. The remaining portions essentially consist of small amounts of compounds related to Tiacumicin B (including, but not limited to Lipiarmicin A4 and Cetone C-19). Preparations of this type are described in detail in PCT Application PCT / US03 / 21977, which has an international publication number of WO 2004/014295 A2. However, for non-human use only, crude OPT-80 containing less than 70% of R-Tiacumicin B (with respect to the total antibiotic substance, by HPLC assay) can be used. According to the present invention, compounds with the structure of Formula VII are provided: Formula VII wherein: X is selected from lower alkyl, and wherein the term "lower alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to two carbon atoms, including methyl, ethyl, n-propyl , isopropyl, and the like; and Y is selected from OH or a ketone (= 0), and Z is selected from H or lower alkyl and wherein the term "lower alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to five carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and the like. Preferred compounds of the invention are compounds of Formula VII wherein X is methyl or ethyl, Y is ketone (= 0) or OH and Z is isopropyl. The most preferred compounds of the invention are compounds of Formula VII wherein X is ethyl, Y is ketone (= 0) or OH, and Z is isopropyl. The most preferred compounds of the invention are compounds of Formula VII wherein X is ethyl, Y is OH R and Z is isopropyl. One embodiment of the present invention is directed toward the discovery that the chiral center in C-19 of Tiacumicin B has a large effect on biological activity.

It has now been found that R-Tiacumicin B, which has an R-hydroxy group in C-19, has significantly higher activity than S-Tiacumicin B and that other compounds related to Tiacumicin B (Lipiarmycin A4 and Cetone C -19). The highest activity is shown by much lower MIC values, which can be seen below in Example 3, Tables 3 and 4 for several strains of C. difficile, S. aureus. E. Faecalis and E. Faecium. This effect of the chiral center C-19 on biological activity is a new and unexpected discovery. In another embodiment of the present invention OPT-80 (which is composed almost entirely of R-Tiacumicin B) has an unusually long post-antibiotic (PAE) effect. This is discussed in Example 4, where it shows that OPT-80 has a PAE of more than 24 hours. This PAE is unexpectedly longer than the usual antibiotic PAE of 1-5 hours. The present invention also relates to the disclosure of pharmaceutical compositions, which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier. Yet another aspect of the invention discloses a method of inhibiting or treating bacterial infections in humans, comprising administering to the patient an amount Therapeutically effective of a compound of the invention alone or in combination with another antibacterial or antifungal agent. Production Macrocycles of 18 members and analogs thereof are produced by fermentation. The cultivation of Dactylosporangium aurantiacum subspecie hamdenensis AB 718C-41 NRRL 18085 for the production of Tiacumicins is carried out in a medium containing carbon sources, inorganic salts and other organic ingredients with one or more absorbents under appropriate aeration and mixing conditions in a sterile environment. The microorganism for producing the active antibacterial agents was identified as belonging to the family Actinoplanaceae, genus Dactylosporangium (Journal of Antibiotics, 1987, 40; 567-574 and US Pat. No. 4,918,174). This has been designated Dactylasporangium aurantiacum subspecies hamdenensis 718C-41. The subculture was obtained from the ARS Patent Collection of the Northern Regional Research Center, United States Department of Agriculture, 1815 North University Street, Peoria, IL. 61604, USA., Where it was assigned accession number NRRL 18085. The characteristics of strain AB 718C-41 are given in the Journal of Antibiotics, 1987, 40, 567-574 and US Patent 4,918,174.

This invention includes the composition of new antibiotic agents, Tiacumicins, by submerged aerobic fermentation of the microorganism Dactylosporangium aurantiacum subspecie ha denensis. The production method is covered by WO 2004/014295 A2, which is incorporated herein by reference. Pharmaceutical Formulation and Administration The pharmaceutical compositions of the Tiacumicin compounds of the present invention, specifically OPT-80 (which is composed almost entirely of the R-Tiacumicin) according to the invention can be formulated substantially immediately after administration or at any predetermined time or period of time after administration. The latter types of compositions are generally known as modified release formulations, which include formulations that create a substantially constant concentration of the drug within the intestinal tract for an extended period of time and formulations that have modified release characteristics based on time criteria or environmental as described in Modified-Release Drug Delivery Technology, ed. M. J. Rathbone, J. Hodgraft and M.S. Roberts. Marcel Dekker, Inc. New York.

Any biologically acceptable oral dosage form may be employed in the methods of the invention. Examples of such dosage forms include, without limitation, chewable tablets, fast-dissolving tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, suppositories, creams, solutions, suspensions, emulsions, tablets, multilayer tablets, bi-layer tablets, capsules, soft gelatine capsules, capsules hard gelatin, osmotic tablets, osmotic capsules, capsules, pills, drops, powders, granules, particles, microparticles, dispersible granules, ingestibles, infusions, healthy bars, preparations, animal feed, cereals, cereal coatings, food, nutritious foods , functional foods and combinations thereof. The preparation of any of the above dosage forms is well known to persons of ordinary skill in the art. Additionally, pharmaceutical formulations can be designed to provide either immediate or controlled release of the antibiotic after reaching the target site. The selection of immediate or controlled release compositions depends on a variety of factors including the susceptibility of the species and the antibiotic of the Gram-positive bacteria being treated and the bacteriostatic / bactericidal characteristics of the bacteria. therapeutic Methods well known in the art for making the formulations are found, for example, in Remington: The Science and Practice of Pharmacy (20th ed.), Ed. A.R. Gennaro, 2000, Lippincott Williams & Wilkins, Philadelphia, or in Encyclopedia of Pharmaceutical Technology, eds, J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York.

The immediate release formulations for oral use include tablets or capsules containing the active ingredient (s) in a mixture with pharmaceutically acceptable, non-toxic excipients. These excipients may be, for example, inert diluents or fillers (for example, sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate. , or sodium phosphate); granulating or disintegrating agents (for example, cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); agglutination agents (eg, sucrose, glucose, mannitol, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, aluminum magnesium silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyleulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants and anti-adhesives (for example, magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils or talc). Other pharmaceutically acceptable agents can be dyes, flavoring agents, plasticizers, humectants, buffering agents and the like are found, for example, in The Handbook of Pharmaceuticals Excipients, third edition, edited by Arthur H. Kibbe, American Pharmaceutical Association Washington DC. Release by controlled dissolution or diffusion can be achieved by proper coating of a tablet formulation, capsule, pill, or granulation of the compounds or by incorporating the compound in an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and / or for example, shellac, beeswax, glycol wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, distearate of glyceryl, glyceryl palmito-stearate, ethylcellulose, acrylic resins, dipolylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3- butylene glycol, ethylene glycol methacrylate and / or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride , polyethylene and / or halogenated fluorocarbon. A controlled release composition may also be in the form of a buoyant tablet or capsule (i.e., a tablet or capsule that, after oral administration, floats on top of the gastric contents for a certain period of time). A floating tablet formulation of the compound (s) can be prepared by granulating a mixture of antibiotic with excipients and 20-75% w / w of hydrocolloids, such as hydroxyethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose. The obtained granules can then be compressed into tablets. In contact with the gastric juice, the tablet forms a water-impermeable gel barrier around its surface. This gel barrier takes part in maintaining a density of less than one, thereby allowing the tablet to remain floating in the gastric juice. Other useful controlled release compositions are known in the art (see example, U.S. Patent Nos. 4,946,685 and 6, 261, 601). A modified release composition may be comprised of a compression coated core whose geometric configuration controls the release profile of the encapsulated antibiotic. By varying the geometry of the nucleus, the release profile of the antibiotic can be adjusted to follow an order of zero, first order or a combination of these orders. The system can also be designed to release more beneficial agents at the same time, each having a different release profile (see, for example, US Patent Nos. 4,111,202 and 3,279,995). Formulations targeting the Tiacumicin compounds of the present invention can also be prepared, specifically OPT-80 (which is composed almost entirely of R-Tiacumicin), which releases particular regions of the intestinal tract. The Tiacumicin compounds of the present invention, specifically OPT-80, can be encapsulated in an enteric coating that prevents degradation of release and that release occurs in the stomach, but that it dissolves easily in moderately acid or pH neutral environment. of the small intestine. A targeted formulation for the release of the antibiotic to the colon, using technologies such as time-dependent, pH-dependent, or enzymatic erosion of the polymer matrix or coating. The targeted release properties of the Tiacumicin compounds of the present invention, specifically OPT-80 (which is composed almost entirely of R-Tiacumicin B) containing the formulation can be modified by other means. For example, the antibiotic can be formed as a complex by inclusion, ionic association, hydrogen bonding, hydrophobic bonding, or by covalent bonding. In addition, polymers or complexes susceptible to enzymatic or microbial lysis can also be used as means for releasing the drug. The encapsulation in microspheres of the compounds of Tiacumicina of the present invention, specifically the OPT-80 (which is composed almost entirely of R-Tiacumicina B) is another pharmaceutical formulation useful for the liberation of the antibiotic directed to the objective. The microspheres containing the antibiotic can be used alone for the release of the antibiotic, or as a component of a two-step release formulation. Suitable step-wise release formulations may consist of acid-stable microspheres, which encapsulate the compounds of the present invention, specifically OPT-80 (which is composed almost entirely of R-Tiacumicin B) to be released later in the lower intestinal tract mixed with an immediate release formulation to release the antibiotic to the stomach and upper duodenum. The microspheres can be manufactured by any suitable method, or from any pharmaceutically acceptable material. Particularly useful are the proteinoid microspheres (see, for example, U.S. Patent Nos. 5,601,846 and 5,792,451) and the microspheres containing PLGA (see for example, U.S. Pat. Nos. 6,235,224 or 5,672,659). Other polymers commonly used in the formation of microspheres include, for example,? -e-caprolactone, poly (e-caprolactone-Co-DL-lactic acid), poly (DL-lactic acid), poly (DL-acid) lactic-Co-glycolic acid) and poly (s-caprolactone-Co-glycolic acid) (see, for example, Pitt et al., J. Pharm. Sci., 68: 1534, 1979). The microspheres can be manufactured by methods well known in the art including spray drying, coacervation, and emulsification (see for example, Davis et al., Microsphere and Drug Therapy, 1984, Elsevier, Benoit et al., Biodegradable icrospheres: Advances in Production Technologies, Chapter 3, ed. Benita, S, 1996, Decay, New York, Microencapsulation and Related Drug Processes, Ed.

Deasy, 1984, Decker, New York; US Patent No. 6, 365, 187). The powders, dispersible powders or granules suitable for the preparation of aqueous solutions or suspensions of the Tiacumicin compounds of the present invention, specifically OPT-80 (which is composed almost entirely of R-Tiacumicin B) by the addition of water are convenient dosage forms for oral administration. The formulation as a suspension provides the active ingredient in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing agents or humectants are, for example, naturally occurring phosphatides (for example, leeitin or condensation products of ethylene oxide with a fatty acid, a long-chain aliphatic alcohol or a partial ester derived from fatty acids) and a hexitol or a hexitol anhydride (e.g., polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate and the like). Suitable suspending agents are, for example, sodium carboxymethyl cellulose, methyl cellulose, sodium alginate, and the like. EXAMPLES The following examples are provided by way of description of specific embodiments of the present invention without intending to limit in any way the scope of the invention.

Example 1- Exact Structure of R-Tiacumicin B The exact structure of R-Tiacumicin B (the component most active major of the OPT-80) is shown below in the Formula IV. The X-ray crystal structure of R-Tiacumicin B It was obtained from a parallelepiped crystal, colorless (0.08 x 0.14 x 0.22 mm) developed in methanol and shows as an ORTEP diagram in Figure 1. This structure X-ray confirms the structure shown in Formula IV.

The official chemical name is 3- [[[6-Deoxy-4-0- (3, 5-dichloro-2-ethyl-4,6-dihydroxybenzoyl) -2-O-methyl-β-D-mannopyranosyl] oxy] - methyl] -12 (R) - [[6-deoxy-5-C-methyl-4-0- (2-methyl-l-oxopropyl) -β-D-lixo-hexopyranosyl] oxy] - 11 (S) -et il-8 (S) -hydroxy-18 (S) - (1 (R) -hydroxyethyl) -9, 13, 15-trimethyloxacyclooctadeca-3, 5,9,13,15-pentaeno-2 -one.

OH Formula IV Example 2 - Analytical Data of OPT-80 and Substances Related The analytical data of OPT-80 (which is composed almost entirely of R-Tiacumicin, which is the component most active of OPT-80) and three related compounds (S-Tiacumicin B, Lipiarmicin A4, and Cetone C-19) are summarized down. The structures of these compounds are shown in the formula VIII and in Table 2 below.

Formula VIII Table 2: Structure of R-Tiacumicin B (the largest component most active of OPT-80) and related substances Compound X and Z R-Tiacumicin B Ethyl (R) -OH Isopropyl S-Tiacumicin B Ethyl (S) -OH Isopropyl Lipiarmicin A4 Methyl (S) -OH Isopropyl Cetone C-19 Ethyl = 0 Isopropyl Analytical data of R-Tiacumicin B Melting point 166-169 ° C (white needle of isopropanol); [a] D20 -6.9 (c 2.0, MeOH); MS m / z (ESI) 1079.7 (M + Na) +; NMR NMR XH XH (400 MHz, CD3OD) d 7.21 (d, IH), 6.59 (dd, IH), 5.95 (ddd, IH), 5.83 (br s, IH), 5.57 (t, IH), 5.13 (br d, IH), 5.09 (t, IH), 5.02 (d, IH), 4.71 (m , IH), 4.71 (br s, IH), 4.64 (br s, IH), 4.61 (d, IH), 4.42 (d, IH), 4.23 (m, IH), 4.02 (penteto, IH), 3.92 ( dd, IH), 3.73 (m, 2H), 3.70 (d, IH), 3.56 (s, 3H), 3.52-3.56 (m, 2H), 2.92 (m, 2H), 2.64-2.76 (m, 3H) , 2.59 (heptet, IH), 2.49 (ddd, IH), 2.42 (ddd, IH), 2.01 (dq, IH), 1.81 (s, 3H), 1.76 (s, 3H), 1.65 (s, 3H), 1.35 (d, 3H), 1.29 (m, IH), 1.20 (t, 3H), 1.19 (d, 3 H), 1.17 (d, 3H), 1.16 (d, 3 H), 1.14 (s, 3H) , 1.12 (s, 3H), 0.87 (t, 3H); 13 C NMR (100 MHz, CD3OD) d 178.4, 169.7, 169.1, 154.6, 153. 9, 146.2, 143.7, 141.9, 137.1, 137.0, 136.4, 134.6, 128.5, 126.9, 125.6, 124.6, 114.8, 112.8, 108.8, 102.3.97.2, 94.3, 82.5, 78.6, 76.9, 75.9, 74.5, 73.5, 73.2, 72.8, 71.6, 70.5, 68.3, 63.9, 62.2, 42.5, 37.3, 35.4, 28.7, 28.3, 26.9, 26.4, 20.3, 19.6, 19.2, 18.7, 18.2, 18.2, 17.6, 15.5, 14.6, 14.0, 11.4.

Analytical data of S-Tiacumicin B.

Formula II (C-19 ketone) Formula V (S-Tiacumicin B) NaBH 4 (9 eq, 48 mg) was added in three portions to a solution of ketone C-19 (150 mg) in 3 mL of MeOH. After 1 hour, saturated NH 4 Cl solution was added. The mixture was extracted with CHC13, and then concentrated. The S-Tiacumicin B was purified by YMC-pack ODS-A 75x30mm I.D. column (H20: eOH: AcOH 28: 72: 1) yielding 35 mg pure of pure S-Tiacumicin B. MS m / z 1074.5 (M + NH 4) +; NMR of XH (400 MHz, CDC13) d 7.15 (d, J = 11.4 Hz, IH), 6.58 (dd, J = 14.1, 11.4 Hz, IH), 5.82 (ddd, J = 14.1, 10.6, 3.5 Hz, IH) ), 5.78 (s, IH), 5.40 (dd, J = 7.8, 7.8 Hz, IH), 5.15 (dd, J = 9.5, 9.5 Hz, IH), 5.01 (d, J = 9.9 Hz, IH), 5.01 (d, J = 9.9 Hz, IH), 4.77 (ddd, J = 5.8, 5.3, 5.3 Hz, IH), 4.68 (d, J = 11.6 Hz, IH), 4.65 (br s, IH), 4.62 (br s, IH), 4.42 (d, J = 11.6 Hz, IH), 4.28 (br s, IH), 4.07-3.97 (m, 2H), 3.74-3.58 (m, 4H), 3.61 (s, 3H), 3.52 (dq, J = 9.5, 5.8 Hz, IH), 3.08 (dq, J = 12.6, 6.1 Hz, IH), 3.01 (dq, J = 12.6, 6.1 Hz, IH), 2.77-2.65 (m, 2H), 2.60 (heptet, J = 6.9 Hz, IH ), 2.55-2.44 (m, 3H), 1.95-1.84 (ra, IH), 1.80 (s, 3H), 1.76 (s, 3H), 1.66 (s, 3H), 1.34 (d, J = 5.8 Hz, 3H), 1.29-1.24 (m, IH), 1.27 (d, J = 6.6 Hz, 3H), 1.21 (t, J = 6.1 Hz, 3H), 1.19 (d, J = 6.9 Hz, 3H), 1.18 ( d, J = 6.9 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.84 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) d 177.4, 170.1, 168.8, 157.6, 152.8, 144.4, 143.1, 141.1, 136.7, 136.2, 134.9, 133.8, 128.7, 125.7, 125.2, 123.0, 113.9, 107.5, 107.2, 101.7, 94.9, 92.6, 80.8, 79.2, 76.6, 74.8, 73.5, 72.7, 71.9, 71.7, 70.2, 70.1, 69.5, 63.5, 62.3, 41.5, 36.6, 34.3, 29.5, 28.2, 26.2, 26.0, 19.4, 19.3, 18.9, 18.5, 17.8, 17.3, 15.3, 14.1, 13.7, 11.1; Analytical data of Lipiarmicin A4 MS m / z 1060.5 (M + NH 4) +; NMR of XH (400 Hz, CDC13) d 7.12 (d, J = 11.6 Hz, IH), 6.59 (dd, J = 14.1, 11.6 Hz, IH), 5.85 (br s, IH), 5.83 (ddd, J = 14.1, 10.6, 4.8 Hz, IH), 5.47 (dd, J = 8.3, 8.3 Hz, IH), 5.12 (dd, J = 9.6, 9.6 Hz, IH), 5.00 (d, J = 10.1 Hz, IH), 4.98 (br d, J = 10.6 Hz, IH), 4.75-4.69 (m, IH), 4.68 (d, J = 11.4 Hz, IH), 4.66 (br s, IH), 4.62 (br s, IH), 4.40 (d, J = 11.4 Hz, IH), 4.26 (br s, IH), 4.07-4.00 (m, IH), 4.02 (br d, J = 3.3 Hz, IH), 3.75-3.61 (m, 4H) , 3.62 (s, 3H), 3.55 (dq, J = 9.6, 6.1 Hz, IH), 2.82-2.45 (m, 6H), 2.60 (s, 3H), 2.07-1.97 (m, IH), 1.92 (s, 3H), 1.81 (s, 3H), 1.67 (s, 3H), 1.32 (d, J = 6.1 Hz, 3H), 1.30-1.22 (m, IH), 1.21 ( d, J = 6.6 Hz, 3H), 1.19 (d, J = 7.1 Hz, 3H), 1.18 (d, J = 7.1 Hz, 3H), 1.15 (s, 3H), I.10 (s, 3H), 0.83 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHZ, CDC13) d 177.4, 170.5, 168.9, 157.8, 153. 0, 144.3, 140.9, 137.7, 137.0, 136.3, 134.6, 134.4, 129.1, 127.9, 125.3, 123.2, 114.5, 107.4, 107.0, 101.8, 94.7, 92.5, 80.3, 79.6, 76.7, 74.9, 73.5, 72.7, 71.9, 71.6, 70.2, 70.1, 69.1, 63.6, 62.3, 41.9, 36.9, 34.4, 28.8, 28.2, 25.9, 20.0, 19.3, 19.0, 18.6, 18.5, 17.8, 17.2, 15.5, 13.8. 11.2; Analytical data of Cetone C-19 S m / z 1072.5 (M + NH4) +; NMR of XH (400 MHz, CDC13) 5 7.27 (d, J = 11.4 Hz, IH), 6.61 (dd, J = 14.7, 11.4 Hz, IH), 5.91 (ddd, J = 14.7, 9.1, 5.8 Hz, IH) ), 5.83 (s, IH), 5.31 (dd, J = 7.9, 7.9 Hz, IH), 5.14 (dd, J = 9.7, 9.7 Hz, IH), 5.06 (d, J = 10.6 Hz, IH), 5.00 (d, J = 10.1 Hz, IH), 4.98 (dd, J = 7.1, 4.8 Hz, IH), 4.67 (d, J = II.9 Hz, IH), 4.66 (br s, IH), 4.61 (br s, IH), 4.42 (d, J = 11.9 Hz, IH), 4.30 (br s, IH), 4.02 (br d, J = 3.3 Hz, IH), 3.63-3.60 (m, 4H), 3.62 (s, 3H), 3.51 (dq, J = 9.7, 6.1 Hz, IH), 3.09 (dq, J = 14.4, 7.3 Hz, IH) , 3.03 (dq, J = 14.4, 7.3 Hz, IH), 2.76-2.50 (m, 6H), 2.21 (s, 3H), 1.93-1.87 (m, IH), 1.87 (s, 3H), 1.75 (s) , 3H), 1.63 (s, 3H), 1.32 (d, J = 6.1 Hz, 3H), 1.27-1.22 (m, IH), 1.21 (t, J = 7.3 Hz, 3H), 1.19 (d, J = 7. 1 Hz, 3H), 1.18 (d, J = 7.1 Hz, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 0.84 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) d 205.5, 177.4, 170.1, 166.9, 157.6, 152.8, 145.7, 143.1, 142.0, 137.1, 136.8, 135.5, 133.7, 128. 3, 124.8, 124.0, 122.8, 113.9, 107.3, 107.2, 101.3, 94.8, 92. 4, 80.4, 77.7, 76.6, 74.7, 73.5, 72.6, 71.8, 71.7, 70.2, 70. 0, 63.0, 62.3, 41.5, 36.5, 34.3, 29.6, 28.1, 26.2, 26.1, 26. 0, 19.2, 18.9, 18.5, 17.8, 17.3, 15.2, 14.0, 13.3, 11.0 Example 3: Biological Activity MIC values determined for several strains of C. díffícile OPT-80 (which is composed almost entirely of R-Tiacumicin B) and its related compounds were tested against C. difficile. The MIC values were reported below in Table 3. As we can see, the OPT-80 was specifically active when compared to S-Tiacumicin B and Lipiarmicin A4.

Table 3: MIC versus C. difficile strains Strains of C. OPT-80 S- Lipiarmicin C-difficile ketone (compound Tiacumicin A4 19 almost entirely of R-Tiacumicin B) ATCC 9689 0.03 0.125 0.06 0.06 ATCC 43255 0.125 1 0.5 0.5 ATCC 17857 0.03 0.25 0.06 nd LC # 1 0.125 1 0.5 0.5 (clinical isolate) MIC values determined for several microorganisms OPT-80 (which is composed almost entirely of R-Tiacumicin B) and its related compounds were tested against several other pathogens. The MIC values are reported below in Table 4. As we can see, the OPT-80 was especially active when compared to S-Tiacumicin B and to Lipiarmicin A4. Table 4: MIC (g / ml) against other microorganisms # of ID Organism OPT-80 (compound S-Tiacumicin Lipiarmicin Strain almost entirely B A4 of R-Tiacumicin B) 1 S. aureus 4 64 8 (ATCC 29213) 2 S. aureus 4 64 16 (MRSA) 3 S. aureus 4 64 8 (MRSA) 4 E. faecalis 2 8 2 (ATCC) 5 E. faecalis 4 32 16 Resistant to Vane. 6 E. faecalis 1 16 4 Resistant to Vane. 7 E. faecalis 1 8 4 Resistant to Vane. 8 E. faecalis 1 32 32 Resistant to Vane.

Example 4: Post-Antibiotic Effect of OPT-80 in C. difflcile The post-antibiotic effect (PAE) of OPT-80 (which is composed almost entirely of R-Tiacumicin B) was measured against two strains of C. difficile , ATCC 43255 and a clinical isolate, LC3. Additionally, vancomycin and rifampin were tested versus LC3. The PAE at 4x MIC was observed extremely long: greater than 24 hours for both strains. Due to the long duration of this effect, an exact PAE was not calculated. Vancomycin on the other hand had a more normal PAE of less than one hour when used at 4x the MIC versus the LC3 strain. Example 5: In Vivo Activity of OPT-80 The in vitro efficacy of OPT-80 (which is composed almost entirely of R-Tiacumicin B), metronidazole and vancomycin were tested versus 110 genetically distinct clinical isolates of C difficile via agar dilution. The MIC data are presented in Tables 5 and 6. Table 5. Geometric mean, MIC ranges, MIC50 and MICgo values for OPT-80 against 110 clinical isolates of C. difficile, vancomycin and metronidazole, in g / mL. Geometric average range MIC50 MIC90 OPT-80 0.015-0.25 0.08 0.125 0.125 Metronidazole 0.025-0.5 0.15 0.25 0.25 Vancomycin 0.06-4 0.8 1 1 Table 6. Raw MIC data for OPT-80, vancomycin (VAN) and metronidazole (MTZ) versus 110 clinical isolates of C. difficile, in g / mL.

ORG ID OPT-80 MTZ VAN ORG ID OPT-80 MTZ VAN Al 1535 0.125 0.25 1 COI 4652 0.25 0.125 1 AB1 832 0.06 0.125 1 CP1 5491 0.125 0.25 1 DI 1360 0.03 0.25 1 61 5930 0.03 0.25 1 The 816 0.06 0.125 1 63 6029 0.25 0.25 0.06 Fl 1015 0.125 0.125 1 64 5940 0.125 0.25 1 Gl 1077 0.125 0.125 1 65 5967 0.06 0.25 0.5 11 1389 0.125 0.125 1 66 6366 0.015 0.125 0.5 Jl 5971 0.06 0.25 1 67 6367 0.125 0.25 1 J7 4224 0.03 0.125 1 68 6368 0.03 0.125 0.06 J9 4478 0.06 0.125 1 69 6370 0.25 0.25 0.5 Kl 4305 0.125 0.25 0.5 70 6376 0.125 0.25 2 K14 5780 0.125 0.125 1 71 6379 0.125 0.25 1 Ll 1423 0.125 0.125 0.5 72 6380 0.125 0.25 2 NI 471 0.125 0.125 0.5 73 6382 0.25 0.25 1 01 1861 0.06 0.125 1 75 6388 0.125 0.125 0.5 Rl 397 0.125 0.125 1 76 6389 0.125 0.25 0.5 R6 6015 0.015 0.25 2 77 6390 0.06 0.125 1 VI 1521 0.125 0.125 0.5 78 6392 0.015 0.03 0.5 Wl 3931 0.125 0.5 1 80 6327 0.125 0.125 0.5 XI 1890 0.125 0.125 1 81 6328 0.125 0.125 0.5 Yl 5639 0.06 0.125 0.5 82 6329 0.06 0.03 0.5 Y2 1459 0.06 0.125 1 83 6330 0.06 0.125 0.5 Zl 3036 0.03 0.125 1 84 6331 0.125 0.25 0.5 AA2 4380 0.015 0.125 1 85 6332 0.06 0.125 1 AB2 1725 0.06 0.125 1 86 6333 0.03 0.125 0.5 AC1 1546 0.06 0.125 1 87 6334 0.125 0.125 0.5 AF1 1808 0.125 0.125 0.5 88 6335 0.125 0.25 0.5 AGI 3044 0.125 0.125 1 89 6336 0.25 0.5 1 AHI 3430 0.125 0.25 0.5 90 6338 0.125 0.125 1 AJI 1557 0.06 0.125 1 91 6339 0.125 0.125 1 AL1 1753 0.06 0.125 0.5 93 6341 0.125 0.125 1 AN1 464 0.125 0.125 0.5 94 6343 0.015 0.06 0.5 AOl 287 0.125 0.125 1 95 6347 0.125 0.125 1 ORG ID OPT-80 MTZ VAN ORG ID OPT-80 MTZ VAN ASI 4099 0.125 0.125 1 96 6348 0.06 0.125 0.5 ATI 1216 0.125 0.125 1 97 6349 0.25 0.125 1 AVI 941 0.25 0.125 0.5 98 6350 0.125 0.5 1 CJ1 893 0.125 0.025 1 101 6354 0.015 0.06 1 AW1 4501 0.125 0.125 1 102 6355 0.016 0.125 1 BE1 4307 0.125 0.25 1 103 6068 0.06 0.125 1 BH1 4506 0.06 0.06 0.5 104 6060 0.03 0.25 1 BU 1675 0.125 0.125 1 105 6071 0.03 0.125 0.5 BK1 4291 0.125 0.125 0.5 106 6078 0.03 0.25 0.5 BL1 716 0.125 0.125 1 107 6079 0.06 0.125 0.5 BM1 1453 0.06 0.125 1 109 6274 0.015 0.125 1 BN1 1322 0.125 0.25 1 111 6279 0.03 0.125 1 BR1 1321 0.06 0.125 1 112 6280 0.06 0.125 0.5 BT1 706 0.06 0.125 1 113 6304 0.06 0.125 1 BV1 1183 0.125 0.25 1 114 386 0.06 0.125 4 BW1 3130 0.125 0.125 1 115 5985 0.015 0.25 2 BX1 4271 0.125 0.25 1 116 5702 0.06 0.125 1 CN1 667 0.25 0.25 1 117 6026 0.06 0.125 2 CB1 1584 0.25 0.125 1 120 6057 0.03 0.25 1 CF1 5922 0.125 0.125 1 121 6072 0.06 0.25 0.5 CG1 1566 0.125 0.125 1 122 6111 0.25 0.25 0.5 CL1 3851 0.25 0.125 1 100 6353 0.125 0.25 1 Example 6: Activity of OPT-80 Compared Against Species Selected Anaerobes The in vitro activity of the OPT-80 against 350 was determined anaerobic organisms. The experimental procedure for which was outlined in Antimicrobial Agents and Chemoterapy, 2004, 48: 4430-4434, which is hereby incorporated as reference in its entirety.

All organisms, including strains of C. difficile were isolated separately and were not related to clonal way. All gram-negative and gram-positive strains of quality control recommended by NCCLS were included with each run: in each case, the results (where they were available) were in the range.

The results of the MIC test are presented in Table 7. Table 7 MICs (g / mL) of the OPT-80 Organism MIC50 MIC90 MIC Bacteroides fragilis (19) 64- > 128 > 128 > 128 Species of the group B. fragilis, no 64- > 128 > 128 > 128 fragilis (38) Species Prevotella / porphyromonas 16- > 128 > 128 > 128 (42) Fusobacterium nucleatum (14) 64- > 128 > 128 > 128 Fusobacterium mortiferum (10) 64- > 128 > 128 > 128 Species fusobacterium, 16- > 128 > 128 > 128 miscellaneous (14) Peptostreptococcus tetradius (16) 0.25-1.0 1.0 1.0 Peptostreptococcus asaccharolyticus 0.25-1.0 0.5 1.0 (15) Peptostreptococcus anaerobius (15) < 0.016-0.03 < 0.016 < 0.016 Finegoldia magna (15) 0.25-2.0 1.0 1.0 Micromonas micros (14) < 0.016-0.06 0.03 0.06 Peptostreptococcus prevotii (3) 0.25-1.0 NA NA Propionibacterium acnes (20) 0.5-1.0 4.0 4.0 Slow Eggerthella (10) < 0.016-0.06 < 0.016 < 0.03 Miscellaneous gram-positives, < 0.016-16 < 0.125 16 non-spore-forming rods Clostridium perfingrens (35) < 0.016-0.06 < 0.016 0.03 Clostridium difficile (21) < 0.016-0.25 < 0.016 0.125 Clostridium tertium (10) < 0.016-0.06 < 0.016 0.03 Clostridium species (19) < 0.016-0.06 < 0.016 0.03 Example 7; In Vitro Activities of OPT-80 Against Intestinal Bacteria The in vitro activity of OPT-80 against intestinal bacteria was evaluated. The experimental procedure for which was outlined in Antimicrobial Agents and Chemoterapy, 2004, 48: 4898-4902, which is hereby incorporated by reference in its entirety. The antimicrobial concentration ranges were selected to encompass and exceed the levels that would be achieved in the intestine (to the extent that this information is available), subject to the solubility limitations of the drugs in the test medium. The concentration range of the OpT-80 used during the test was 0.03 μ9 /? T? 1 at 1024 g / ml. For the analysis, the tested bacteria was generally placed in gender, species or other groups with at least 10 isolates. Ranges and MICs at which 50 and 90% isolates were inhibited were determined except for organisms with less than 10 tested strains, for which only ranks were reported (Table 8). OPT-80 had good activity against most organisms in the form of rods or rods that do not form spores, gram-positive, anaerobic and gram-positive anaerobic cocci. OPT-80 also showed good activity against enterococci and staphylococci.

Table 8. In Vitro Activity of OPT-80 against 453 bacterial isolates OTHER MODALITIES All references discussed above are hereby incorporated by reference in their entirety for all purposes. While this invention has been shown and particularly described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims .

Claims (36)

1. CLAIMS 1. A composition characterized by comprising
2. 70% - 100% of a compound of Formula VII
3. Formula VII wherein X is a lower alkyl selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl; and Y is OH or ketone (= O); and Z is H or a lower alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and pentyl. The composition of claim 1, characterized in that said composition further comprises 0% -30% of compounds related to Tiacumicin B. 3. The composition of claim 1, characterized in that said composition comprises 75% of Formula VII .
4. 4. The composition of claim 1, characterized in that said composition comprises 80% of Formula VII.
5. The composition of claim 1, characterized in that said composition comprises 85% of Formula VII.
6. 6. The composition of claim 1, characterized in that said composition comprises 90% of Formula VII.
7. The composition of claim 1, characterized in that said composition comprises 95% of Formula VII.
8. The composition of claim 1, characterized in that said X is methyl or ethyl; and Y is OH or ketone (= O); and Z is isopropyl.
9. 9. The composition of claim 8, characterized in that said X is ethyl; and Y is OH or ketone (= 0); and Z is isopropyl.
10. The composition of claim 9, characterized in that said X is ethyl; and Y is OH; and Z is isopropyl.
11. 11. A composition characterized in that it is comprised of 70-100% of a compound of Formula IV
12. Formula IV. The composition of claim 11, characterized in that said composition further comprises 0-30% of compounds related to Tiacumicin B.
13. 13. The composition of claim 12, characterized in that said compounds related to the
14. Tiacumicin B are selected from the group consisting of Lipiarmycin A4 and Cetone C-19. The composition of claim 12, characterized in that said composition comprises (a) = 90% of said compound of Formula IV; and (b) = 10% of said compounds related to Tiacumicin B.
15. 15. The composition of claim 14, characterized in that said compounds related to the

    Tiacumicin B are selected from the group consisting of Lipiarmycin A4 and Cetone C-19.
16. 16. A pharmaceutical composition characterized in that it is comprised of: (a) 70% -100% of a compound of Formula VII wherein X is a lower alkyl selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl; and Y is OH or ketone (= 0); and Z is H or a lower alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and pentyl; and (b) 0% - 30% of the compounds related to Tiacumicin B; and (c) a pharmaceutically acceptable carrier.
17. 17. The pharmaceutical composition of claim 16, characterized in that it further comprises an additional agent selected from the group consisting of an antimicrobial agent and an antifungal agent.
18. 18. The pharmaceutical composition of claim 16, characterized in that said X is methyl or ethyl; and Y is OH or ketone (= 0); Y

    Z is isopropyl.
19. 19. The pharmaceutical composition of claim 18, characterized in that said X is ethyl; and Y is OH or ketone (= 0); and Z is isopropyl.
20. 20. The pharmaceutical composition of claim 19, characterized in that said X is ethyl; and Y is OH; and Z is isopropyl.
21. The pharmaceutical composition of claim 20, characterized in that said compounds related to Tiacumicin B are selected from the group consisting of Lipiarmycin A4 and Cetone C-19.
22. 22. A pharmaceutical composition characterized in that it is comprised of: (a) 70% -100% of a compound of Formula IV (b) 0% -30% of compounds related to Tiacumicin B; and (c) a pharmaceutically acceptable carrier.
23. 23. The pharmaceutical composition of claim 22, characterized in that said pharmaceutical composition is composed of
24. (a) = 90% of said said compound of Formula IV; and (b) = 10% of said compounds related to Tiacumicin B; and (c) said pharmaceutically acceptable carrier. The pharmaceutical composition of claim 23, characterized in that said compounds related to Tiacumicin B are selected from the group consisting of Lipiarmycin A4 and Cetone C-19.
25. 25. A method for treating bacterial infections in a mammal, characterized in that it comprises administering to said mammal a pharmaceutical composition comprising a therapeutically effective amount of said pharmaceutical composition of claim 16.
26. 26. The method of claim 25, characterized in that said X is methyl or ethyl; and Y is OH or ketone (= 0); and Z is isopropyl.
27. 27. The method of claim 26, characterized in that said X is ethyl; and Y is OH or ketone (= O); and Z is isopropyl.
28. 28. The method of claim 27, characterized in that said X is ethyl; and Y is OH; and Z is isopropyl.
29. 29. The method of claim 28, characterized in that said compounds related to Tiacumicin B are selected from the group consisting of Lipiarmycin A4 and Cetone C-19.
30. 30. The method of claim 28, characterized in that the pharmaceutical composition is composed of said pharmaceutical composition of claim 23.
31. 31. The method of claim 30, characterized in that said compounds related to Tiacumicin B are selected from the group consisting of Lipiarmicin A4 and C-19 ketone.
32. 32. The method of claim 30, characterized in that said pharmaceutical composition has a MIC value that is significantly lower than the MIC values of the compounds related to Tiacumicin B.
33. The method of claim 32, characterized in that said compounds related to Tiacumicin B are selected from the group consisting of Lipiarmycin A4, and Cetone C-19.
34. 34. The method of claim 32, characterized in that said MIC value is determined using bacteria selected from the group consisting of C. difficile, S. aureus, E. faecalis, and E. faeciu.
35. 35. The method of claim 30, characterized in that said pharmaceutical composition has a post-antibiotic effect (PAE) of more than 24 hours.
36. 36. The method of claim 30, characterized in that said pharmaceutical composition further comprises an additional agent selected from the group consisting of an antimicrobial agent and an antifungal agent.