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Mutasynthesis of lincomycin derivatives with activity against drug-resistant staphylococci

Dana Ulanova1, Jitka Novotná, Yvona Smutná

  • 1Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídenská 1083, Prague 4, Czech Republic 142 20. ulanova@biomed.cas.cz

Antimicrobial Agents and Chemotherapy
|November 18, 2009
PubMed

Insights

Deleting the lincomycin biosynthetic gene lmbX abolished lincomycin production. Supplementing with precursor derivatives yielded novel, potent lincosamides, including 4-pentyl-4-depropyllincomycin, which showed enhanced activity against resistant Staphylococcus strains.

Area of Science:

  • Microbiology
  • Biochemistry
  • Synthetic Biology

Background:

  • Lincomycin is a crucial antibiotic for treating bacterial infections.
  • Understanding its biosynthesis pathway is key to developing novel analogs.
  • Genetic manipulation of Streptomyces lincolnensis offers a route to modified antibiotic production.

Purpose of the Study:

  • To investigate the role of the lmbX gene in lincomycin biosynthesis.
  • To engineer a mutant strain for the production of novel lincomycin derivatives.
  • To evaluate the antimicrobial activity of these novel derivatives.

Main Methods:

  • Gene deletion of lmbX in Streptomyces lincolnensis ATCC 25466.
  • Complementation experiments to confirm gene function.
  • Feeding precursor derivatives to the mutant strain.
  • Antimicrobial susceptibility testing against clinical Staphylococcus isolates.

Main Results:

  • Deletion of lmbX completely abolished lincomycin production.
  • Complementation confirmed lmbX's role in 4-propyl-L-proline biosynthesis.
  • The mutant produced 4'-butyl-4'-depropyllincomycin and 4'-pentyl-4'-depropyllincomycin without lincomycin contamination.
  • 4'-pentyl-4'-depropyllincomycin exhibited higher activity than lincomycin against resistant Staphylococcus strains.

Conclusions:

  • The lmbX gene is essential for lincomycin biosynthesis.
  • Genetic engineering of Streptomyces lincolnensis enables the production of novel, potent lincomycin analogs.
  • 4'-pentyl-4'-depropyllincomycin represents a promising candidate for combating lincosamide-resistant bacterial infections.

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