19-Deformyl-4'-deoxydesmycosin (TMC-016): Synthesis and biological properties of a unique 16-membered macrolide antibiotic.

Fujiwara, Tatsuro; Watanabe, Hideyuki; Kogami, Yuji; Shiritani, Yoshinori; Sakakibara, H.

doi:10.7164/antibiotics.42.903

“…As a bioconversion product, desmycosin, which is the degradation product of tylosin, has been isolated by the feeding culture method from the tylosin biosynthetic intermediate 5‐ O ‐mycaminosyl‐tylonolide (OMT) [8]. Furthermore, the hybrid compounds isolated from the cultured agar plate with 19‐deformyl‐5‐ O ‐mycaminosyl‐tylonolide, which is a derivative of OMT, added to M7A21 were determined to be 19‐deformyl‐desmycosin [16] and a novel compound 19‐deformyl‐12,13‐epoxydesmycosin [8], which was a further oxidation product similar to mycinamicin I. Therefore, the feeding culture with M7A21 would be powerful tools to perform combinatorial biosynthesis for the production of new macrolide antibiotics.…”

Section: Resultsmentioning

confidence: 99%

The targeted inactivation of polyketide synthasemycAVin the mycinamicin producer,Micromonospora griseorubida, and a complementation study

Anzai

¹

,

Ishii

²

,

Yoda

³

et al. 2004

FEMS Microbiology Letters

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Mycinamicin is a 16-membered macrolide antibiotic produced by Micromonospora griseorubida A11725, which shows strong antimicrobial activity against gram-positive bacteria. Recently, the nucleotide sequences of the mycinamicn biosynthetic gene cluster in M. griseorubida have been completely determined. Mycinamicin non-producer M7A21 was isolated by mycAV inactivation, which encodes the module 7 of mycinamicin polyketide synthase (PKS) required for the biosynthesis of the mycinamicin biosynthetic intermediate protomycinolide-IV (PML-IV). When the bioconversion to mycinamicin II (M-II) from PML-IV was performed using M7A21 and the feeding culture method, the productivity of M-II was the same as that of M-II in wild-type strain A11725. p446M7 containing mycAV was constructed using the Escherichia coli-Streptomyces shuttle vector pGM446. The mycinamicin productivity of M7A21 was restored by the introduction of p446M7 into the M7A21 cell, but almost all p446M7 was integrated into the chromosome of M7A21 because the plasmid was unstable in M7A21. The feeding culture and the introduction of the complement gene for M7A21 would be powerful tools to perform combinatorial biosynthesis for the production of new macrolide antibiotics.

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“…As a bioconversion product, desmycosin, which is the degradation product of tylosin, has been isolated by the feeding culture method from the tylosin biosynthetic intermediate 5-O-mycaminosyl-tylonolide (OMT) [8]. Furthermore, the hybrid compounds isolated from the cultured agar plate with 19-deformyl-5-O-mycaminosyl-tylonolide, which is a derivative of OMT, added to M7A21 were determined to be 19deformyl-desmycosin [16] and a novel compound 19deformyl-12,13-epoxydesmycosin [8], which was a further oxidation product similar to mycinamicin I. Therefore, the feeding culture with M7A21 would be powerful tools to perform combinatorial biosynthesis for the production of new macrolide antibiotics.…”

Section: Bioconversion Of Mycinamicin Biosynthetic Intermediatesmentioning

confidence: 99%

The targeted inactivation of polyketide synthase in the mycinamicin producer, , and a complementation study

Anzai¹,

Ishii²,

Yoda³

et al. 2004

FEMS Microbiology Letters

View full text Add to dashboard Cite

Mycinamicin is a 16-membered macrolide antibiotic produced by Micromonospora griseorubida A11725, which shows strong antimicrobial activity against gram-positive bacteria. Recently, the nucleotide sequences of the mycinamicn biosynthetic gene cluster in M. griseorubida have been completely determined. Mycinamicin non-producer M7A21 was isolated by mycAV inactivation, which encodes the module 7 of mycinamicin polyketide synthase (PKS) required for the biosynthesis of the mycinamicin biosynthetic intermediate protomycinolide-IV (PML-IV). When the bioconversion to mycinamicin II (M-II) from PML-IV was performed using M7A21 and the feeding culture method, the productivity of M-II was the same as that of M-II in wild-type strain A11725. p446M7 containing mycAV was constructed using the Escherichia coli-Streptomyces shuttle vector pGM446. The mycinamicin productivity of M7A21 was restored by the introduction of p446M7 into the M7A21 cell, but almost all p446M7 was integrated into the chromosome of M7A21 because the plasmid was unstable in M7A21. The feeding culture and the introduction of the complement gene for M7A21 would be powerful tools to perform combinatorial biosynthesis for the production of new macrolide antibiotics.

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“…We used tylosin (1) as a carbonyl compound as well as a carboxylic acid component (compound 22) after oxidation with sulfamic acid and sodium chlorite [23]. Both reactions yielded the expected products 23-25 in acceptable yields.…”

mentioning

confidence: 98%

New macrocycles with potent antituberculosis activity accessed by one-pot multicomponent reactions

Kim

¹

,

Huang

²

,

Wang

³

et al. 2013

Chem Heterocycl Comp

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Based on modeling studies, we hypothesized that tylosin derivatives without formyl group should rather adopt an erythromycin-like binding mode to the ribosome. Twenty four 16-membered macrocyclic compounds were accessed by multicomponent reactions (Gewald, Ugi) of tylosin and investigated for their antituberculosis activity. The best compound was twice as active as tylosin and might thus be a good starting point for further optimization of biological properties.

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19-Deformyl-4'-deoxydesmycosin (TMC-016): Synthesis and biological properties of a unique 16-membered macrolide antibiotic.

Cited by 16 publications

References 7 publications

The targeted inactivation of polyketide synthasemycAVin the mycinamicin producer,Micromonospora griseorubida, and a complementation study

The targeted inactivation of polyketide synthasemycAVin the mycinamicin producer,Micromonospora griseorubida, and a complementation study

The targeted inactivation of polyketide synthase in the mycinamicin producer, , and a complementation study

New macrocycles with potent antituberculosis activity accessed by one-pot multicomponent reactions

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