0001 This invention relates to a compound named Amycomycin, which is obtainable by cultivation of the microorganism Amycolatopsis species ST101170 (DSM 12216), and to its pharmaceutically-acceptable salts and derivatives. The present invention further relates to a process for the production of Amycomycin, to the use of Amycomycin and its pharmaceutically-acceptable salts and derivatives as pharmaceuticals, in particular to their use as antibiotics, and to pharmaceutical compositions comprising Amycomycin or a pharmaceutically-acceptable salt or derivative thereof. 0002 Methicillin resistant Staphylococcus aureus (MRSA) infections are known to be predominant in infectious conditions such as wounds and burns. Vancomycin and teicoplanin, which belong to the glycopeptide class, are the only two antibiotics clinically used for the treatment of MRSA infections. However, due to the recent emergence of vancomycin- and teicoplanin-resistant strains, these infections are reported to have become life-threatening and fatal. An intensive search for a structurally-different class of compounds active against these vancomycin- and teicoplanin-resistant strains has, therefore, been initiated. For instance, methylsulfomycin I, a cyclic thiopeptide, has been described earlier (EP-A-0818539 filed Jul. 11, 1996) as an antibiotic active against vancomycin- and teicoplanin-resistant strains. 0003 It has now been found that a novel compound named Amycomycin has antibiotic activity. The present invention thus relates to a compound of the formula: 2

0004 and to pharmaceutically-acceptable salts and derivatives thereof, such as esters, ethers and other obvious chemical equivalents, including all stereoisomeric forms and all tautomeric forms. 0005 Amycomycin has a characteristic tetramic acid moiety with a highly oxygenated C45-side chain. It has the molecular formula C65H115NO18 and is obtainable by cultivation of the microorganism Amycolatopsis species ST101170 (DSM 12216) under aerobic conditions in a nutrient medium containing sources of carbon and nitrogen, followed by isolation and purification in a customary manner. The microorganism ST101170 belongs to the order of Actinomycetales, genus Amycolatopsis, and was deposited on Jun. 4, 1998, with the German Collection of Microorganisms and Cell Cultures (DSMZ-Deutsche Sammlung von Mikroorganismen und Zelikulturen GmbH), Braunschweig, Deutschland and has been given the accession number DSM No. 12216. 0006 The present invention further provides a process for the production of the compound named Amycomycin from Amycolatopsis species ST101170, its mutants and variants, under aerobic conditions in a nutrient medium containing one or more sources of carbon and one or more sources of nitrogen and optionally nutrient inorganic salts and/or trace elements, followed by isolation of the compound and purification in a customary manner. 0007 Mutants and variants of the microorganism ST101170 may also be able to synthesize the compound according to the present invention. Such mutants may be produced in a known manner by physical means, for example, irradiation such as with ultraviolet- or X-rays, or with chemical mutagens, such as ethylmethylansulfonate (EMS), 2-hydroxy-4-methoxy-benzophenone (MOB) or N-methyl-N-nitro-N-nitrosoguanidine (MNNG). 0008 The screening for suitable mutants and variants that can produce the compound according to the invention can be confirmed by determination of the biological activity of the active compounds accumulated in the culture broth, for example, by testing the antibacterial action, in particular against vancomycin-resistant strains (see Table 2 below). 0009 Preferred carbon sources suitable for aerobic fermentation are assimilable carbohydrate and sugar alcohols, such as glucose, lactose or D-mannitol as well as carbohydrate-containing natural products such as malt extract. Suitable sources of nitrogen are, for example, amino acids, peptides and proteins, including their degradation products such as peptones or tryptones, meat extract, ground seeds, for example, of maize, white beans, soya or the cotton plants, distillation residues from alcohol production, meat meal and yeast extracts, but also ammonium salts and nitrates. Suitable inorganic salts, which the nutrient solution may contain, are, for example, chlorides, carbonates, sulfates or phosphates of the alkaline metals or alkaline earth metals, ion, zinc, colbalt or manganese. 0010 The formation of Amycomycin proceeds well, for example, in a nutrient medium comprising about 0.5 to 5% starch (soluble), preferably 1 to 2%, about 0.5 to 5% glucose, preferably 1 to 3%, about 0.5 to 5% glycerin, preferably 1 to 2%, about 0.1 to 0.5% corn steep liquor, preferably 0.2 to 0.3%, about 0.2 to 1% peptone, preferably 0.4 to 0.6%, about 0.1 to 0.5% yeast extract, preferably 0.2 to 0.4%, about 0.05 to 0.2% sodium chloride, preferably 0.1 to 0.2% and about 0.1 to 0.5% CaCO3, preferably 0.2 to 0.3%. These amounts are based on the weight of the whole nutrient medium. 0011 The growth of ST101170 is carried out aerobically, for example, in liquid medium with shaking or stirring in shake flasks or laboratory fermenters, optionally with the introduction or air or oxygen. Growth by fermentation can be carried out, for example, in sterile wide-necked bottles or round-bottomed flasks of various volumes, in glass fermenters or V2A-steel tanks. 0012 The growth of ST101170 may be carried out at temperatures between about 20 C. and about 35 C., preferably between about 25 C. and about 30 C. and pH between 4 and 10, preferably between 6 and 8. Under these conditions, the microorganism is grown in general over a period of 20 to 200 hours, preferably 24 to 150 hours. 0013 Growth is advantageously carried out in several stages. Firstly, one or more pre-cultures may be prepared in a liquid nutrient medium. A main culture, the actual production medium, is then inoculated with the pre-culture in, for example, a volume ratio of 1:10. The pre-culture is obtained, for example, by inoculating a nutrient medium with sporified mycelium and allowing growth for about 20 to about 120 hours, preferably 24 to 90 hours. The sporified mycelium can be obtained, for example, by allowing the microorganism to grow for about 1 to about 40 days, preferably about 5 to about 12 days, on a solid or liquid nutrient medium such as yeast-malt agar or potato-dextrose agar. 0014 The course of fermentation and the formation of Amycomycin can be monitored by methods known to the skilled person such as by measuring the biological activity of the culture broth in bioassays or by chromatographic methods such as thin-layer chromatography (TLC) or high-pressure liquid chromatography (HPLC). 0015 The compound Amycomycin is present in the culture filtrate as well as in the mycelium. Usually, however, the highest amount is present in the mycelium. The compound can be isolated using known separation techniques. Thus, it can be recovered from the culture filtrate by, for example, filtration or centrifugation. The filtrate can be extracted with a water-immiscible solvent such as 1-butanol, ethyl acetate, chloroform, dichloromethane or the like, preferably 1-butanol or ethyl acetate. 0016 The active material also can be recovered from mycelium by extraction with a water miscible solvent such as methanol, acetone, acetonitrile, n-propanol or iso-propanol, preferably methanol or acetone or a water immiscible solvent such as tert-butanol, ethyl acetate, chloroform, dichloromethanol or the like, preferably tert-butanol or ethyl acetate. 0017 The extraction of the culture filtrate may be carried out within a wide pH range. It is preferable, however, for the extraction to be carried out in a neutral or weakly acidic medium, preferably at a pH of between 4 and 9. The organic extract may be concentrated in vacuum and dried to give the active crude material. 0018 The isolation or purification of the compound Amycomycin may be carried out in a known manner taking into consideration the chemical, physical and biological characteristics of the natural compound. 0019 One method of isolation of Amycomycin according to the invention is solution partition in a manner known to one skilled in the art. 0020 Another method of purification of the Amycomycin is by chromatography on adsorption resins such as Diaion HP-20 (Mitsubishi Casei Corp., Tokyo), Amberlite XAD 7 (Rohm and Haas, USA), Amberchrom CG (Toso Haas, Philadelphia, USA), or similar resins. The separation can be carried out within a wide pH range. Preferably the pH range is 1 to 9, more preferably 2 to 8. Also suitable are numerous reverse phase supports, example RP8 and RP18, such as have been generally publicized in the context of high-pressure liquid chromatography (HPLC). A further possibility for purification of the compound according to the invention consists in the use of so-called normal-phase chromatographic supports such as silica gel, or Al2O3 (alumina) or others in a manner known to one skilled in the art. Many eluents are suitable for this, such as dichloromethane, chloroform, methanol, ethyl acetate, acetone, petroleum ether, or combinations thereof. The pH can be varied, for example, by addition of triethylamine. 0021 An alternative isolation process of the compound Amycomycin is the use of molecular sieves such as Fractogel TSK HW-40, Sephadex LH-20, and others in a manner known per se. Moreover, it also is possible to recover the compound Amycomycin from the crude material by crystallization. Suitable therefor are, for example, organic solvents and their mixtures, anhydrous or with the addition of water. 0022 An additional process for the isolation and purification of the compound according to the invention consists in the use of anion-exchangers, preferably in the pH range of from 7 to 10 and cation-exchangers, preferably in the pH range of from 3 to 7. Particularly suitable for this purpose is the use of buffer solutions to which amounts of the organic solvents have been added. 0023 Additionally, counter-current chromatography using a biphasic eluent system made up of two or more solvents such as water, methanol, ethanol, butanol, isopropanol, acetone, dichloromethane, ethyl acetate, or petroleum ether, is a possible purification process. 0024 The compound Amycomycin or chemical derivatives thereof can be converted to the corresponding pharmacologically-acceptable salts by methods known to one skilled in the art. 0025 Pharmacologically-acceptable salts of compounds according to the invention are inorganic or organic salts such as are described in Remington's Pharmaceutical Sciences (17. Edition, page 1418 (1985)). Possible salts are alkali metal salts, ammonium salts, alkaline earth metal salts, salts with physiologically-acceptable amines and salts with inorganic or organic acids such as HCl, HBr, H2SO4, maleic acid and fumaric acid. 0026 Obvious chemical equivalents of compounds according to the present invention are compounds that have a slight chemical difference but which have the same or similar activity or that, under mild conditions, can be converted to the compounds according to the present invention. Examples of obvious chemical equivalents are esters, ethers, amino derivatives, complexes or adducts of the compounds according to the invention. 0027 Esters may be prepared, for example, by reacting Amycomycin with carboxylic acids in the presence of reagents such as dicyclohexylcarbodiimide (DCC), or by treating the compound with an acylating agent such as an acid chloride. 0028 Ethers may be prepared, for example, from Amycomycin by reaction with alkylating agents under basic conditions. 0029 Other methods for the preparation of esters and ethers are given in the literature, for example, in Advanced Organic Synthesis, 4th Edition, J. March, John Wiley & Sons., 1992. 0030 Chemical equivalents may be stable complexes with metal ions, e.g., transition metals like La3, Sm3, Eu3, Gd3, which are typical for tetramic acid derivatives and may be prepared by the methods given in the literature (K. Tanaka et. al., Chem. Pharm. Bull. 1979, 27, 1901. K. Matsuo, Chem. Pharm. Bull. 1980, 28, 2494). 0031 The double bonds of the alkyl side chain may be reduced by the methods given in the literature, for example in P. N. Rylander, Hydrogenation Methods, Academic Press, New York (1985), Chapter 2, or may be hydrohalogenated by methods described by H. O. House in Modern Synthetic Reactions, W. A. Benjymin, Inc., New York (1972), pp 446-452. Hydroxylated derivatives may be produced by reaction of the double bonds with reagents like OsO4 as described in the literature, e.g., in Chem. Rev. 80: 187 (1980). 0032 Derivatives also may be formed by conversion of the double bonds into epoxides by oxidation, e.g., with MCPBA as described in Advanced Organic Synthesis, 4th Edition, J. March, John Wiley & Sons., 1992. 0033 The physical-chemical as well as the spectroscopic characteristics of the compound Amycomycin according to the invention are as follows: 0034 Appearance: colorless solid, soluble in methanol, DMSO, pyridine 0035 Molecular formula: C65H115NO18

1HPLC (High PressureColumn:Purospher Star RP.18eLiquid Chromatography):(Merck), 55 4 mm, 3 mEluent:CH3CN/0,01% H3PO4 (85%)Gradient:Time (min)% CH3CN0.005.03.0095.05.0095.06.005.010.005.0Flow:2 ml/minTemp.:40 C.Detection:210 nm, 254, 280, 320, 380tR:2.67 minMolecular weight:1198.64 DaHR-FAB-MS:1220.801187 M Na1H- and 13C-NMR:see Table 1UV/VIS:MeGH, max (log ) 229 nm (3.29),281 (3.16)

0036

2TABLE 1Chemical shift of Amycomycin in MeOD at 300 K.1H13C10.8614.7620.9720.8331.8931.2043.4182.2051.7039.5560.7713.6373.5480.1981.6536.3290.8612.71101.4331.20111.4436.46123.7571.98131.62/1.5444.79143.7472.22151.58/1.3736.46161.63/1.1429.27171.5140.69180.9015.70193.7072.90271.51/1.4642.12284.0766.31291.5242.12303.8072.54314.3373.26326.62142.1833138.47341.8312.7535206.04364.2141.00371.1417.77385.36128.3739138.72401.6912.75413.9880.54421.6441.25430.888.02443.5973.88451.4936.46461.62/1.3223.50471.55/1.3233.34483.8075.09491.7442.71500.7711.92513.4177.87521.6136.46530.8612.75541.55/1.3231.37551.61/1.4436.46563.7771.83571.6744.53583.9271.12592.3037.54605.84 (b)131.7 (c)61(c)621.8213.8163(c)64(c)653.24 (b)27.9166(c)67(c)68(c)695.50 (b)119.3 (c)703.0926.52711.1024.31721.1024.31(b) Broad signals (c) These signals are not visible. C60 und C69 could only be assigned with the HMQC-spectrum.

0037 Amycomycin has extraordinary antibacterial activity, particularly against gram-positive bacteria such as, for example, Staphylo- and Enterococci. Minimum inhibitory concentrations of Amycomycin against a wide range of bacteria are given in Table 2 below. Lately, these strains have proven increasingly to be problem strains, i.e., those microorganisms that have become resistant to existing antibiotics. The superiority of the present compound in relation to other antibiotics is shown, for example, in the inhibition of vancomycin- and teicoplanin-resistant strains such as, for example, E. faecalis, E. faecium or E. gallinarium. 3TABLE 2Minimum Inhibition Concentration (mg/L) (micro-dilutions test)CODEAmycomycinVancomycinGram-positive StrainS.aureus011HT3oxa S ery S0.080.3S.aureus011HT18ATCC 13709 Smith0.080.3S.epidermidis012GO20oxa S ery S tet R0.30.6S.aureus011HT1nov R< 0.040.08S.aureus011DU5nov R tet R0.080.15S.aureus011CB20oxa R ery Rc tet R0.080.15S.aureus011GO71ofl S oxa R ery S tet R0.150.6S.aureus011GO64ofl R oxa R ery Rc tet R0.31.2S.epidermidis012GO42oxa R0.31.2Staph.coag.negative012HT5ofl R oxa R tet R0.150.6S.aureus011GR91pri R oxa R ery R nov R1.21.2S.pyogenesO2A1SJ1van S ery Rc0.30.15S.pyogenesO2A1UC1van S ery S0.60.15S.pyogenesO2A1FI6ery R0.60.08Strepto gr.GO2G0CB2tet R rif R nov R0.60.15S.pneumoniae030BI2ery R0.150.15S.milleriO2milGR12ery S van S1.20.3S.mitisO2mitGR16ery Ri van S1.20.3E.faeciumO2D3AP9nov S van R ery S tei R0.6>40E.faeciumO2D3HT12tei R van R ery R tet R0.6>40E.faeciumO2D3IP2tei R van R ery R tet RND>40E.faeciumO2D3HM3nov S van A ery R tei R1.2>40E.gallinariumO2D0HM8van C tet R ery S1.2>40E.faecalisO2D2HM9nov R van B ery R tei S2.5>40E.faecalisO2D2UC5ATCC 29212 nov R2.52.5E.faecalisO2D2DU18tet R nov R1.20.3E.faecalisO2D2HT10nov R van S tet R1.20.6Gram-negative StrainE.coliDB10 250IP5ery S fuc S nov SND>40P.aeruginosa1771 391HT2>40>40P.aeruginosa1771m 391HT3mutant permable>40>40

0038 Amycomycin and its pharmaceutically-acceptable salts and derivatives can be administered to animals, preferable to mammals, and in particular to humans as pharmaceuticals on their own, in mixtures with one another, and in the form of pharmaceutical compositions that permit parenteral or other modes of administration. Accordingly, the present invention also relates to Amycomycin and its pharmaceutically-acceptable salts and derivatives for use as pharmaceuticals and to the use of Amycomycin and its pharmaceutically-acceptable salts and derivatives for the production of medicaments having antibacterial activity. The present invention further relates to pharmaceutical compositions which contain an effective amount of Amycomycin and/or one or more pharmaceutically-acceptable salts and/or derivatives thereof, together with a pharmaceutically-acceptable carrier. 0039 Amycomycin can be administered enterally (oral route), parenterally (intravenously or intramuscularly) rectally or locally (topically). Pharmaceutical compositions that contain Amycomycin or a pharmaceutically-acceptable salt or derivative thereof with other pharmaceutically-active substances can be prepared by mixing the active compounds with one or more pharmacologically-tolerated auxiliaries and/or excipients, and converting the mixture into a suitable pharmaceutical form for administration, such as, solutions, powders (tablets, capsules including microcapsules), ointments (creams or gels), liposome preparations, lipid complexes, coloidal dispersions, or suppositories. 0040 Possible auxiliaries and/or excipients for formulations of this type are the pharmaceutically-customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavor corrigents, colorants and/or buffer substances. 0041 As is customary, the pharmaceutical formulation and the method of administration, as well as the dosage range, that are suitable in a specific case depend on the species to be treated and on the state of the respective condition or disease, and can be optimized using methods known in the art. As an example, a dose of 0.001-10 mg, preferably 0.1-5 mg, more preferably 1.0 mg for a body weight of approx. 75 kg may be suitable. The dose should at least be sufficient to produce the desired effect.

0042 The following are illustrative examples of the present invention but do not limit the scope thereof:

EXAMPLE 1

Preparation of Seed Material 0043 100 ml of nutrient solution (4 g/l yeast extract, 15 g/l soluble starch, 1 g/l K2HPO4, 0.5 g/l MgSO47 H2O filled with water to 1000 ml, pH 7.0 before sterilization) in a sterile 300 ml Erlenmeyer flask were inoculated with the strain Amycolatopsis species ST101170 (DSM 12216) and incubated for 5 days at 28 C. and at 180 rpm on a rotary shaker. 1.5 ml of this culture was subsequently diluted with 1.5 ml of 99% glycerin and stored at 20 C.

EXAMPLE 2

Preparation of Culture or Pre-culture of Amycolatopsis Species ST101170 (DSM 12216) in Erlenmeyer Flasks 0044 A sterile Erlenmeyer flask containing 100 ml of the following nutrient medium: 10 g/l starch solution, 10 g/l glucose, 10 g/l glycerin 99%, 2.5 g/l corn steep fluid or liquor, 5 g/l peptone, 2 g/l yeast extract, 1 g/l NaCl, and 3 g/l CaCO3, was inoculated with a loopful of grown culture (same nutrient solution, but with 2% agar) or with 1 ml of a glycerin culture (see Example 1) and incubated on a shaker at 180 rpm and at 28 C. Maximum production of the compound Amycomycin was reached after 72 hours. 0045 A 72 hour old submersed culture (produced according to the described process for the shake culture, Example 1, but with the following medium: 15 g/l glucose, 15 g/l soyameal, 3 g/l CaCO3 and 5 g/l NaCl, pH 7.5) was sufficient for the inoculation of 10 and 200 L fermenters with an inoculation amount of 10%.

EXAMPLE 3

Production of the Compound Amycomycin 0046 A 200 L fermenter was run with the following parameters: 4Nutrient medium:10 g/L starch10 g/L glucose10 g/L glycerin 99%2.5 g/L cornsteep liquor5 g/L peptone2 g/L yeast extract7 g/L NaCl3 g/L CaCO3pH 7.2 (before sterilization)Inoculum:10% fermenter volumeIncubation time:60 to 80 hoursIncubation temperature:28 C.Agitation:50 rpmAeration:150 L/min

0047 By addition of 1 to 2 ml of an ethanolic polyol solution it was possible to limit foam formation. The production maximum was reached after 69 hours.

EXAMPLE 4

Isolation of the Compound Amycomycin 0048 200 L of the culture solution obtained from Example 3 was centrifuged and the mycelium was exhaustively extracted with methanol. The methanol extract was concentrated to a ratio of approximately 1:10 to obtain a colorless precipitate, which was filtered off. This procedure was repeated until the substance Amycomycin could no longer be detected in the filtrate by reverse phase HPLC. The residue was freeze-dried and subsequently purified by HPLC: 0049 1. Column: Fractogel TSK-HW 40 (4 L, 500100 mm) 0050 Eluent: MeOH 0051 Flow Rate: 20 ml/min 0052 Detection: 204 and 236 nm. 0053 The fractions enriched with Amycomycin eluted after 125 minutes. Fractions were pooled based on reverse phase HPLC (conditions mentioned above). The active pooled fractions with the desired compound were concentrated under vacuum and freeze-dried. 0054 2. Column: Silica Gel 60 (Merck); Erimatech (30020 mm, 100 ml) 5Eluent:A) CH2Cl2B) CH2Cl2:MeOH 9:1C) MeOH.Gradient:min% A% B% C0100001510000350100045010006500100Flow Rate:25 ml/minDetection:236 and 288 nm

0055 The active compound Amycomycin eluted after 42 minutes. Fractions were pooled based on reverse phase HPLC (conditions mentioned above). The active pooled fractions with the desired compound were concentrated in vacuum and freeze-dried. 0056 3. Column: Fractogel TSK-HW 40 (1 L, 50050 mm) 0057 Eluent: MeOH 0058 Flow Rate: 5 ml/min 0059 Detection: 204 and 236 nm 0060 The active component Amycomycin eluted after 112 minutes. 0061 From 200 L fermentation broth, 110 mg of Amycomycin was recovered according to the above process.