Rational design of peptide antibiotics by targeted replacement of bacterial and fungal domains.
Peptide synthetases involved in the nonribosomal synthesis of peptide secondary metabolites possess a highly conserved domain structure. The arrangement of these domains within the multifunctional enzymes determines the number and order of the amino acid constituents of the peptide product. A general approach has been developed for targeted substitution of amino acid-activating domains within the srfA operon, which encodes the protein templates for the synthesis of the lipopeptide antibiotic surfactin in Bacillus subtilis. Exchange of domain-coding regions of bacterial and fungal origin led to the construction of hybrid genes that encoded peptide synthetases with altered amino acid specificities and the production of peptides with modified amino acid sequences.
Stachelhaus
T
T
Biochemie/Fachbereich Chemie, Philipps-University of Marburg, Germany.
Schneider
A
A
Marahiel
M A
MA
D000595:Amino Acid Sequence; D049148:Aminoacylation; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D001407:Bacillus / Q000235:genetics; D001412:Bacillus subtilis / Q000235:genetics; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D003001:Cloning, Molecular; D005798:Genes, Bacterial; D005800:Genes, Fungal; D006461:Hemolysis / Q000187:drug effects; D055666:Lipopeptides; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009876:Operon; D010408:Penicillium chrysogenum / Q000235:genetics; D010453:Peptide Synthases / Q000737:chemistry / Q000235:genetics*; D010456:Peptides, Cyclic; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D014169:Transformation, Bacterial
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D011993:Recombinant Fusion Proteins; C009365:surfactin peptide; D010453:Peptide Synthases; C069542:surfactin synthetase