Engineered biosynthesis of peptide antibiotics

• Published in: Biochemical pharmacology Vol. 52; no. 2; pp. 177 - 186
• Main Authors: Stachelhaus, Torsten, Schneider, Axel, Marahiel, Mohamed A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 26.07.1996; Elsevier Science
• Subjects: Amino Acid Sequence; Anti-Bacterial Agents - biosynthesis; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; domain structure, peptide antibiotics; Drug Design; Drug Resistance, Microbial; Genetic Engineering; Medical sciences; Molecular Sequence Data; non-ribosomal peptide biosynthesis; Peptide Synthases - chemistry; Peptide Synthases - genetics; Peptide Synthases - metabolism; peptide synthetases; Peptides; Pharmacology. Drug treatments; Recombinant Proteins - genetics; peptide synthetases; domain structure, peptide antibiotics; drug design; genetic engineering; non-ribosomal peptide biosynthesis; Drug; Antibiotic; Peptides; Biosynthesis; Genetic engineering; Antibacterial agent; Research and development
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/0006-2952(96)00111-6

In certain bacteria and filamentous fungi, a wide variety of bioactive peptides are produced non-ribosomally on large protein templates, called peptide synthetases. Recently, significant progress has been made towards understanding the modular arrangement of these complex multifunctional enzymes and the mechanisms by which they generate their corresponding peptide products. It has now been established that the synthesis of bioactive peptides and the specification of their sequence are brought about by a protein template that contains the appropriate number and the correct order of activating units (domains). These advances have enabled the development of a technique that permits the construction of hybrid genes encoding peptide synthetases with specifically altered substrate specificities. A programmed alteration within the primary structure of a peptide antibiotic is achieved by the substitution of an amino acid-activating domain in the corresponding protein template at the genetic level by a two-step recombination method. It utilizes successive gene disruption and reconstitution and demonstrates, for the first time, the potential of genetic engineering in the biosynthesis of novel peptide antibiotics. Many organisms, for instance those that cause diseases like tuberculosis and pneumonia, have evolved potent mechanisms of drug resistance. Therefore, the targeted engineering of peptide antibiotics could be one potential strategy for the development of novel drugs that overcome this resistance.