CN110669103A - Double demethyl actinomycin derivatives and application thereof in preparation of drug-resistant bacteria infection resisting drugs - Google Patents

Abstract

The invention discloses a double demethylation actinomycin derivative and application thereof in preparing a drug for resisting drug-resistant bacteria infection. The structural formula of the actinomycin double demethyl derivative Didemactinomycin D is shown as a formula (I),Didemactinomycin X₂the structural formula is shown as a formula (II). The actinomycin demethylation derivatives Didemactinomycin D and Didemactinomycin X with the drug-resistant staphylococcus aureus can be separated from a methyltransferase inactivated mutant strain ZS 0073/delta acnM of an actinomycin D production strain S₂The test result shows that the Didemactinomycin D has good inhibitory activity (MIC is 4-32 ug/mL) on 14 strains of staphylococcus aureus, and compared with actinomycin D, the Didemactinomycin D has greatly reduced toxicity on normal human body cells, thereby showing the important value of the Didemactinomycin D in the development of anti-infective drugs.

Description

Double demethyl actinomycin derivatives and application thereof in preparation of drug-resistant bacteria infection resisting drugs

Technical Field

The invention belongs to the technical field of natural products, and particularly relates to a demethylation derivative of actinomycin, namely, didemethyinomycins, and a preparation method and application thereof.

Background

Actinomycin D is a pigment peptide lactone antibiotic isolated from Actinomycetes by Waskman and Wooddruff as early as 1940. The structure of the compound is composed of chromophore (actinocin, 2-amino-4, 6-dimethylphenyloxyazine-3-one-1, 9-dicarboxyic acid) and two cyclic pentapeptide lactones (alpha ring and beta ring) connected with the chromophore by amide bond, if the amino acid types of the alpha ring and the beta ring are the same, the compound is called iso-actinomycins, and if the amino acid compositions of the alpha ring and the beta ring are different, the compound is called iso-acti nomycins. Actinomycin compounds generally appear as a pronounced orange or red color due to the presence of chromophores. The actinomycin has obvious biological activities of antibiosis, tumor resistance, antivirus and the like. The main action mechanism is that the DNA can penetrate most cell membranes through osmosis and selectively gather in cell nucleus to be used as a target point. The mother nucleus-phenoxazinone chromophore-can be combined with guanine of DNA double helix through hydrogen bond, and the cyclic pentapeptide lactone can be inserted into the minor groove of DNA to increase the stability of combination, thereby inhibiting the replication and transcription of DNA to achieve the effects of antibiosis, anti-tumor and antivirus. In addition, studies have shown that actinomycin D can inhibit tumor cells by affecting nucleic acid synthesis, inducing cell differentiation and apoptosis, affecting the cell cycle, and inhibiting protease activity. The actinomycin D can also specifically target and down regulate the expression of a stem cell transcription factor Sox-2; this protein promotes depletion of the stem cell population, resulting in failure of breast cancer cells to proliferate. The low dose of actinomycin D can also specifically activate p53 gene-dependent transcription to accelerate apoptosis of human tumor cells.

Because of good antibacterial and antitumor activities of actinomycin D, it has been widely used in clinical treatment of various tumors, such as chorionic disease, melanoma, Wilms' tumor (nephroblastoma), malignant endothelial myelopathy and soft tissue sarcoma, and has better curative effect, and is one of the "star drugs" in clinical antitumor drugs. Although actinomycin has good superiority in antibiosis, antivirus and antitumor, it has large toxicity, thus limiting further clinical application. The toxicity to human body is mainly manifested by leucopenia, thrombocytopenia and anemia, and certain toxicity to intestinal tract, mainly causes inappetence, nausea and vomiting, abdominal pain and diarrhea, and can also cause mucositis and red spot and pigment on the skin of patients after administration. Therefore, the modification of the structure of actinomycin or the separation of structural analogs from nature has great profound and important significance for the development of novel actinomycin with high efficiency and low toxicity.

Disclosure of Invention

The first purpose of the invention is to provide two actinomycin demethyl derivatives Didemactinomycins with drug-resistant staphylococcus aureus resistance.

The structural formula of the Didemactinomycin D derivative of actinomycin is shown as a formula (I), and the Didemactinomycin X derivative is shown as a formula (I)₂The structural formula is shown as a formula (II).

The second object of the present invention is to provide a process for producing Didemactinomycins which are actinomycin demethyl derivatives, said Didemactinomycins D and Didemactinomycins X₂Is prepared by separating from a methyltransferase inactivated mutant strain ZS 0073/delta acnM of actinomycin D producing strain S.costaricantus SCSIO ZS0073 from sea source.

Preferably, the specific steps are as follows:

(a) preparing fermentation culture of methyltransferase inactivated mutant strain ZS0073/Δ acnM of actinomycin D producing strain S.costaricanus SCSIO ZS0073 from sea source, and centrifuging fermentation supernatant and mycelium; extracting mycelium with acetone, extracting supernatant with butanone, concentrating acetone extract and butanone extract under reduced pressure to obtain mycelium extract and supernatant extract, and mixing the two extracts to obtain crude extract;

(b) mixing the crude extract obtained in the step (a) with silica gel, and performing normal phase silica gel column chromatography with a chloroform/methanol system gradient of 100: 0; 98: 2; 96: 4; 94: 6; 92: 8; 9: 1; 8: 2; 6: 4; eluting at V/V ratio of 5:5, mixing fraction Fr.3 eluted at chloroform/methanol volume ratio of 96:4 and fraction Fr.4 eluted at chloroform/methanol volume ratio of 94:6, mixing with silica gel, performing normal phase silica gel column chromatography with chloroform/methanol system of 100: 0; 98: 2; 96: 4; 94: 6; 92: 8; 9: 1; 8: 2; 6: 4; gradient elution with a gradient of V/V5: 5, in which fraction Fr3.2 eluted with a chloroform/methanol volume ratio of 98:2 is purified to give Didemactinomycin D and Didemactinomycin X₂。

It is a third object of the present invention to provide the above-mentioned Didemactinomycin D or Didemactinomycin X₂The application in preparing anti-infective drugs or anticancer drugs.

It is a fourth object of the present invention to provide an anti-infective or anticancer agent containing Didemactinomycin D or Didemactinomycin X₂As an active ingredient.

Preferably, the anti-infective drug is a drug resistant staphylococcus aureus drug.

Preferably, the anti-cancer drug is a drug for resisting lung cancer, cervical cancer, liver cancer, breast cancer or rectal cancer.

The fourth object of the present invention is to provide a methyltransferase-inactivated mutant strain ZS0073/Δ acnM of actinomycin D-producing strain S.costaricissus SCSIO ZS0073 of marine origin in the preparation of Didemactinomycin D or Didemactinomycin X₂The use of (1).

The actinomycin demethylation derivatives Didemactinomycin D and Didemactinomycin X with the drug-resistant staphylococcus aureus can be separated from a methyltransferase inactivated mutant strain ZS 0073/delta acnM of an actinomycin D production strain S₂The test result shows that the didemactinomycin D has good inhibitory activity (MIC is 4-32 ug/mL) on 14 strains of staphylococcus aureus, and compared with actinomycin D, the didemactinomycin D has greatly reduced toxicity on normal human body cells, thereby showing the important value of the didemactinomycin D in the development of anti-infective drugs.

The Stremptmeess costaricanus SCSIO ZS0073 disclosed in the literature: research on antibacterial active secondary metabolites of actinomycetes Stremptmesticanus scSIOZS0073 of mangrove actinomycetes [ J ] research and development of natural products, 2017,29(3):410 and 414. the strain also holds by the applicant and ensures release to the public within 20 years from the application date.

A methyltransferase-inactivated mutant ZS0073/Δ acnM of S.costaricanus SCSIO ZS0073 was constructed by knock-out of the methyltransferase in the S.costaricanus SCSIO ZS0073 gene cluster (gene bank No. QAR 15122). (the gene knockout method is described in Gust, B.; Kieser, T.; Chater, K.PCRtargeting system in Streptomyces coelicolor A3 (2); John Innes centre.2002,3, 1-39).

Drawings

FIG. 1 is a HPLC chart showing the production of bisdemethylactinomycin by fermentation of methyltransferase-inactivating mutant strain ZS0073/Δ acnM of actinomycin D-producing strain S.costaricus SCSIO ZS0073 derived from sea, wherein ZS0073-WT is wild-type S.costaricus SCSIO ZS0073/Δ acnM-1, ZS0073/Δ acnM-2, ZS0073/Δ acnM-3 is 3 methyltransferase-inactivating mutant strain ZS0073/Δ acnM, a-actinomycin D;

1-Didemactinomycin D；

FIG. 2 is a crystal diffraction structure of Didematinomycin D;

FIG. 3 shows Didemactinomycin D¹H-¹H COSY and partial HMBC related information.

The specific implementation mode is as follows:

the following examples are further illustrative of the present invention and are not intended to be limiting thereof.

Example 1: knock-out of methyltransferase gene in marine-derived streptomyces s

The streptomycete S.costaricanus SCSIO ZS0073 related by the invention is obtained by separating from the soil of the mangrove forest in the south China sea. And (3) constructing a mutant strain ZS 0073/delta acnM by using the methyltransferase in the insertional inactivation knockout gene cluster. ZS 0073/. DELTA.acnM strains grown on ISP2 medium were inoculated into 250mL triangular flasks containing 50mL ISP2 medium, respectively, and were subjected to fermentation culture at 200rpm at 28 ℃ for seven days. After the fermentation, the medium was extracted with butanone and analyzed by HPLC, and it was found that Didematinomycins were produced by fermentation of ZS 0073/. DELTA.acnM in ISP2 liquid medium (FIG. 1).

The ISP2 culture medium comprises the following components: 4.0g/L glucose, 4.0g/L yeast extract powder, 10g/L malt extract powder, 30g/L sea salt, 20g/L agar powder and water as solvent, and adjusting the pH value to 7.3, wherein the preparation method comprises the steps of uniformly mixing the components, adjusting the pH value and sterilizing;

example 2 isolation and structural identification of Didematinomycins

1. Preparation of fermentation culture of S.costaricanus SCSIO ZS0073 methyltransferase-inactivated mutant ZS0073/Δ acnM

(1) Preparing a seed culture medium and a fermentation culture medium:

the seed culture medium and the fermentation culture medium are respectively a liquid ISP2 culture medium containing sea salt, and the components are as follows: 4.0g/L glucose, 4.0g/L yeast extract powder, 10g/L malt extract powder, 30g/L sea salt, 20g/L agar powder and water as solvent, and adjusting the pH value to 7.3, wherein the preparation method comprises the steps of uniformly mixing the components, adjusting the pH value and sterilizing; the seed culture medium is equally divided into 250mL conical flasks, 50mL of each flask, and sterilized at 115 ℃ for 30min for later use. The culture medium of the amplified fermentation is subpackaged into 1L conical flasks, 200mL of each flask, and sterilized for 30min at 115 ℃ for later use.

(2) Culturing seeds:

the activated methyltransferase-inactivated mutant strain ZS 0073/delta acnM was inoculated into a 250mL conical flask containing 50mL seed medium, and cultured on a shaker at 28 ℃ and 200rpm for 48h to obtain a seed culture solution.

(3) Large-scale fermentation culture:

transferring 50mL of the seed culture solution in the conical flask into a 1L conical flask containing 200mL of fermentation medium, and culturing on a shaker at 28 ℃ and 200rpm for 7 days to obtain a fermentation culture of the methyltransferase inactivated mutant strain ZS 0073/delta acnM.

2. Isolation of Didematinomycins from Methyltransferase-inactivating mutants ZS 0073/. DELTA.acnM fermentation cultures

(1) Extraction of fermentation cultures

Centrifuging the supernatant and thallus of the fermentation culture; extracting mycelium with acetone of equal volume for 3 times, extracting supernatant with butanone of equal volume for 5 times, concentrating under reduced pressure to obtain mycelium extract and supernatant extract, and mixing the two extracts to obtain crude extract;

(2) isolation of the Compound Didemactinomycins

Mixing the crude extract obtained in step (1) with silica gel, performing normal phase silica gel column chromatography, eluting with chloroform/methanol system gradient (100: 0; 98: 2; 96: 4; 94: 6; 92: 8; 9: 1; 8: 2; 6: 4; 5:5, V/V, volume fraction, 500mL) to obtain 9 fractions from Fr.1-Fr.9 in total, mixing Fr.3 and Fr.4, performing normal phase silica gel column chromatography, and eluting with chloroform/methanol system gradient (100: 0; 98: 2; 96: 4; 94: 6; 92: 8; 9: 1; 8: 2; 6: 4; 5:5, V/V, volume fraction, 500mL) to obtain a total fraction Fr.3-Fr.9, a fraction Fr.3 and Fr.4 containing Didemactinomycins250mL) to give a total of 9 fractions Fr.3.1 to Fr3.9 in that order, in which the chloroform/methanol system 98: the fraction Fr.2 eluted at 2v/v was separated and purified by semi-preparative high performance liquid chromatography (mobile phase CH)₃CN/H₂O50% v/v elution at A flow rate of 4.0mL/min), and YMC-Pack ODS-A column (250 mm. times.10 mm,5 μm) was used as A column to give the compounds Didemactinomycin D (retention time 15.2min) and Didemactinomycin X₂(retention time 16.2 min).

Compounds Didematinomycin D and Didematinomycin X of the invention prepared from fermentation cultures of the methyltransferase-inactivating mutant ZS0073/Δ acnM, were analyzed by structural analysis₂The identification results are as follows:

didematinomycin D is a dark red crystal, and its molecular ion peak M/z 1227.6[ M + H ] is shown by its positive electrospray mass spectrum ESI-MS]⁺Theoretical calculation of the formula C₆₀H₈₂N₁₂O₁₆：1226.5972，1249.6[M+Na]⁺(ii) a Nuclear magnetic data (see Table 1) of Didematinomycin D show that Didematinomycin D has 60 carbon atoms and has a molecular formula C, which is presumed by combining its hydrogen spectra with mass spectral data₆₀H₈₂N₁₂O₁₆。¹H-NMR showed that: 4 independent nitrogen methyl groups (delta H2.89, 2.96, 2.89, 2.93).¹³The C-NMR spectrum, combined with its DEPT135, shows that this compound has a signal of 60 carbon atoms: wherein there are 12 sp between delta C160-175²A hybridized carbonyl signal carbon, which binds to the 12N atoms contained in its molecular formula, so the 12 carbonyl groups are presumed to be amide carbonyl carbons; between delta C35-40 there are four sp3 hybridized C signals, which are related according to their HMQC and¹the H-NMR spectrum assumed that the four C's are nitrogen methyl signals. The characteristic signals are basically consistent with the reported data of actinomycin D, and the Didemactinomycin D is reduced by 2C and 4H according to molecular formula analysis; continuing on Didematinomycin D¹H-NMR spectroscopy revealed that Didemactinomycin D gave two more signals at δ H at 7.53(1H, m) and 6 less methyl H signals at δ H2.19, 2.52 than the Chromophore of actinomycin D; from heteronuclear multiple bond correlation spectroscopy (HMBC) we found that delta H6.48 (1H, s) in Didematinomycin D hybridizes with sp2 hybridized C-3 (delta C179.0) (Chromo)The keto group in the phore structure) and the related signals of C-2 (delta C147.9), C-4a (delta C146.1) and C-9a (delta C135.4) prove that the Didemactinomycin D has the related signals¹Delta H6.48 (1H, s) in the H-NMR spectrum is located at the C-4 position in the Chromophore structure; similarly, Δ H7.53 (1H, m) has correlation signals with C-5a (Δ C147.9), C-7(Δ C147.9), C-8(Δ C147.9), C-9a (Δ C147.9), while Δ H7.53 (1H, m)/H-7 and/H-7/H-8 have correlation signals with¹H-¹H-COSY-associated signals (FIG. 3) the above information demonstrates that Δ H7.53 (1H, m) is located at the C-6 position in the Chromophore structure. Thus, Didemactinomycin D was identified as an actinodidemactinomycin D in which two methyl groups were removed at the C-4 and C-6 positions in the chromosome structure. The crystal structure of Didemactinomycin D is shown in FIG. 2.

Didemactinomycin X₂The red powder is obtained, and the positive ion high resolution electrospray mass spectrogram HR-ESI-MS shows that the molecular ion peak is M/z 1241.5870[ M + H ]]⁺Theoretical calculation of C₆₀H₈₁N₁₂O₁₇：1241.5843，m/z 1263.5712[M+Na]⁺Theoretical calculation of C₆₀H₈₀N₁₂O₁₇Na：1263.5662，Didemactinomycin X₂The nuclear magnetic data of (Table 1) shows that Didematinomycin X₂Has 60 carbon atoms, and the molecular formula is presumed to be C by combining the hydrogen spectrum and mass spectrum data₆₀H₈₀N₁₂O₁₇. The nuclear magnetic spectrum of the compound is compared with that of the Didemactinomycin D, and the nuclear magnetic data of the Didemactinomycin D show that the compound is Didemactinomycin X₂Has 60 carbon atoms, and the molecular formula is presumed to be C by combining the hydrogen spectrum and mass spectrum data₆₀H₈₀N₁₂O₁₇Analysis of Didematinomycin D and Didematinomycin X₂The nuclear magnetic data of (1) shows that Didematinomycin X₂The same nuclear magnetic signature as Didemactinomycin D and HMQC correlation is associated with HMBC, but with a formula one oxygen atom more than Didemactinomycin D, two hydrogen atoms less than Didemactinomycin D, and with Didemactinomycin X₂DEPT135 (g) shows a ratio of Didematinomycin D (Δ C22.9, 23.1, 31.0, 32.3, 47.3, 47.6, 51.4, 51.4) to Didematinomycin D (Δ C23.0, 31.0, 32.3, 47.3, 47.6, 51.4, 51.4)The methylene signal is absent, and the carbon spectrum is added with a keto carbon signal delta C208.8. Analysis of heteronuclear multiple bond correlation spectrum (HMBC) we found that delta H6.59(1H, m) and delta C208.8 have obvious correlation signals, and the HMQC correlation spectrum results in delta H6.59(1H, m) and sp located at 2-position of proline (Pro)³The hybridized carbon atom (. delta.C.54.3) has a related signal, belonging to the methine hydrogen signal, and (. delta.H.sub.6.59) (1H, m) has related signals with C-1 (. delta.C.sub.172.7), C-3 (. delta.C.sub.41.9), C-5 (. delta.C.sub.52.8) on proline and H-2/H-3 on proline¹H-¹H-COSY related signal, the above information proves that Didematinomycin X₂Proline with the middle keto carbon δ C208.8 in the β ring, presumably Didemactinomycin X₂Is a derivative of Didematinomycin X in which the methylene group at the 4-position of proline in the D beta ring of Didematinomycin is changed into keto group₂。

TABLE 1 Didematinomycin D and Didematinomycin X₂Is/are as follows¹H-NMR and¹³C-NMR data (CD)₃Cl)

The structure of the target compound Didemactinomycin D separated by the method is shown as a formula (I), and the structure of the Didemactinomycin X is shown as a formula (I)₂The structural formula of the compound is shown as a formula (II).

Example 3 Compounds Didematinomycin D and Didematinomycin X₂Antibacterial activity test analysis for series of staphylococcus aureus

Testing of Compounds Didematinomycin D and Didematinomycin X by Millipore assay₂Inhibiting activity against Staphylococcus aureus. Mueller-Hinton (MH) broth culture medium is selected to culture a series of staphylococcus aureus. And the sample solution is prepared before the experimental bacteria grow well. Preparing a sample and positive control concentration, wherein the positive control is ampicillin, kanamycin or vancomycin. Was prepared in 3200. mu.g/mL with the sample, and was dissolved in DMSO. Using a line gun, 92. mu.L of sterile MH broth was added to a 96-well plate in the first column, 50. mu.L of MH broth was added to each of the remaining columns, and columns 11 and 12 (50. mu.L of sterile MH broth was added) were used as positive and negative controls, respectively, and the plate was covered with a lid after labeling. Pipette 8 μ L (starting concentration 128 ug/mL; 4 μ L if starting concentration 64; 2 μ L if starting concentration 32) of the formulated sample or positive control and add to the first column. The gun volume was set to 50 μ L and the first column of test drug was carefully pipetted 4-5 times up and down to mix well, while preventing over-forceful spillage. Sucking 50 μ L from the first row, adding into the corresponding second row, sucking 4-5 times carefully, mixing, sucking 50 μ L, and adding into the third row. And so on until diluted to column 10. 50 μ L from column 10 was discarded. A volume of sterile MH broth was poured into a sterile petri dish with a lid. After diluting overnight-cultured cells with MH broth 1000, 50. mu.L of the diluted test bacterial suspension was added to each well of 1-11 columns. At this time, the drug concentrations in the first to tenth columns were 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25. mu.g/mL, respectively. Cover the lid, shake gently, place in 37 ℃ incubator for culture. After culturing for 16-18h, making positive control on the 11 th column and blank control on the 12 th column, and observing the experimental result according to the control result to determine the MIC value of each sample. Each sample was done in 3 replicates. The results of the activity test showed that Didemactinomycin D was effective against 14 strains of Staphylococcus aureus: staphylococcus aureus ATCC 29213, MRSA, s. aureus Sau 29213, s.aureus Sau 1862, s.ureus Sau 669, s.aureus Sau 991, s.aureus 6917, s.aureus 16162, s.aureus 718306, s.aureus 745524, s.aureus mrsgde 4P037P, s.aureus (cfr) GDQ6P01MIC values for 2P, S.simulans AKA1, S.aureus CCAM3093 ranged from 4-32. mu.g/mL, while Didemactinomycin X₂The inhibitor only shows inhibitory activity to two strains of staphylococcus aureus S.aureus 745224 and 718306, and the MIC values of the inhibitor are both 8 mu g/mL, and specific results are shown in Table 2. The result of the cytotoxic activity test shows that the cytotoxic activity of the Didemactinomycin D is greatly reduced compared with that of the actinomycin D (the result is shown in the table 3), and the important potential of the Didemactinomycin D in the development of anti-infective drugs is shown.

TABLE 2 Didematinomycin D and Didematinomycin X₂MIC (. mu.g/mL) value of

TABLE 3 cytotoxic Activity (IC) of Didemactinomycin D₅₀,μM，48h)

Note: DDACM is Didemactinomycin D; ACM-D is actinomycin D; DOX is Doxorubicin; CIS is Cisplatin; a549, human lung cancer cell line; HeLa, human cervical cancer cell line; HepG2, human liver cancer cell line; MCF7, human breast cancer cell line; SW1116, human colorectal cancer cell line; l02, human normal liver cell line; huvec-12, a normal human umbilical vein endothelial cell line.

Claims (10)

1. Didematinomycin D or Didematinomycin X derivatives of bisdemethylactinomycin₂The structural formula of the Didemactinomycin D is shown as the formula (I); didematinomycin X₂The structural formula is shown as a formula (II).

2. Didematinomycin D or Didematinomycin X₂The method of producing said Didemactinomycin D or Didemactinomycin X₂Was isolated from S.costaricanus SCSIO ZS0073/Δ acnM methyl transferase-inactivated mutant.

3. The preparation method according to claim 2, comprising the following steps:

(a) preparing fermentation culture of methyltransferase inactivated mutant strain ZS0073/Δ acnM of actinomycin D producing strain S.costaricanus SCSIO ZS0073 from sea source, and centrifuging fermentation supernatant and mycelium; extracting mycelium with acetone, extracting supernatant with butanone, concentrating acetone extract and butanone extract under reduced pressure to obtain mycelium extract and supernatant extract, and mixing the two extracts to obtain crude extract;

(b) mixing the crude extract obtained in the step (a) with silica gel, and performing normal phase silica gel column chromatography with a chloroform/methanol system gradient of 100: 0; 98: 2; 96: 4; 94: 6; 92: 8; 9: 1; 8: 2; 6: 4; eluting at V/V ratio of 5:5, mixing fraction Fr.3 eluted at chloroform/methanol volume ratio of 96:4 and fraction Fr.4 eluted at chloroform/methanol volume ratio of 94:6, mixing with silica gel, performing normal phase silica gel column chromatography with chloroform/methanol system of 100: 0; 98: 2; 96: 4; 94: 6; 92: 8; 9: 1; 8: 2; 6: 4; gradient elution with a gradient of V/V5: 5, in which fraction Fr3.2 eluted with a chloroform/methanol volume ratio of 98:2 is purified to give Didemactinomycin D and Didemactinomycin X₂。

4. Didematinomycin D or Didematinomycin X according to claim 1₂The application in preparing anti-infective drugs or anticancer drugs.

5. The use of claim 4, wherein the anti-infective agent is an anti-drug resistant Staphylococcus aureus agent.

6. The use of claim 4, wherein the anti-cancer agent is an agent against lung cancer, cervical cancer, liver cancer, breast cancer or rectal cancer.

7. An anti-infective or anticancer agent comprising Didemactinomycin D or Didemactinomycin X as claimed in claim 1₂As an active ingredient.

8. The medicament of claim 7, wherein the anti-infective agent is an anti-drug resistant Staphylococcus aureus agent.

9. The drug of claim 7, wherein the anticancer agent is an agent against lung cancer, cervical cancer, liver cancer, breast cancer or rectal cancer.

10. Methyltransferase-inactivating mutants of the strain S.costaricanus SCSIO ZS0073/Δ acnM for the preparation of Didematinomycin D or Didematinomycin X according to claim 1₂The use of (1).

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