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Novel avermectins produced by mutational biosynthesis.

C J Dutton1, S P Gibson, A C Goudie

  • 1Central Research Division, Pfizer Ltd., Kent, England.

The Journal of Antibiotics
|March 1, 1991
PubMed
Summary
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Novel avermectins were created using a Streptomyces avermitilis mutant by supplying specific carboxylic acids. These new avermectins demonstrate broad-spectrum antiparasitic activity, offering potential for new treatments.

Area of Science:

  • Microbial biotechnology
  • Medicinal chemistry
  • Parasitology

Background:

  • Avermectins are potent antiparasitic compounds produced by Streptomyces avermitilis.
  • Natural avermectin production is dependent on specific branched-chain fatty acid precursors.
  • A mutant strain, ATCC 53568, is deficient in synthesizing these essential precursors.

Purpose of the Study:

  • To produce novel avermectin analogs with diverse C-25 substituents.
  • To investigate the utility of mutational biosynthesis for generating avermectin derivatives.
  • To evaluate the antiparasitic activity of these novel avermectins.

Main Methods:

  • Utilizing a Streptomyces avermitilis mutant (ATCC 53568) deficient in isobutyric and S-2-methylbutyric acid synthesis.

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  • Supplementing the fermentation media with various carboxylic acids or their biosynthetic precursors.
  • Characterizing the resulting avermectin products via chemical analysis.
  • Assessing the antiparasitic efficacy of the novel avermectins.

    • Main Results:

    • Successful preparation of avermectins with diverse novel C-25 substituents.
    • Demonstration of mutational biosynthesis as a viable strategy for avermectin analog production.
    • Identification of novel avermectins exhibiting broad-spectrum antiparasitic activity.

    Conclusions:

    • Mutational biosynthesis in Streptomyces avermitilis is an effective method for generating avermectin analogs.
    • Supplementation with specific carboxylic acids enables the production of avermectins with tailored C-25 modifications.
    • The novel avermectins possess significant potential as broad-spectrum antiparasitic agents.