Molecular engineering approaches to peptide, polyketide and other antibiotics

  title={Molecular engineering approaches to peptide, polyketide and other antibiotics},
  author={Richard H. Baltz},
  journal={Nature Biotechnology},
  • R. H. Baltz
  • Published 1 December 2006
  • Biology, Chemistry, Engineering
  • Nature Biotechnology
Molecular engineering approaches to producing new antibiotics have been in development for about 25 years. Advances in cloning and analysis of antibiotic gene clusters, engineering biosynthetic pathways in Escherichia coli, transfer of engineered pathways from E. coli into Streptomyces expression hosts, and stable maintenance and expression of cloned genes have streamlined the process in recent years. Advances in understanding mechanisms and substrate specificities during assembly by polyketide… 

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Modular construction of a functional artificial epothilone polyketide pathway.

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Genetic Engineering of Acidic Lipopeptide Antibiotics

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Recombinatorial biosynthesis of polyketides

A strategy to construct recombinant Streptomyces strains to produce these polyketides is described and the critical steps of mobilizing large biosynthetic clusters and producing new linear cloning vectors are illustrated by experimental data.

Tools for metabolic engineering in Streptomyces

The main aim of this review is to summarize and discuss the published literature on tools for metabolic engineering of Streptomyces over the last decade.

Identification and Biotechnological Application of Novel Regulatory Genes Involved in Streptomyces Polyketide Overproduction through Reverse Engineering Strategy

Sequential targeted gene manipulation involved in polyketide biosynthetic reguation synergistically provided an efficient and rational strategy for Streptomyces strain improvement.

Antibiotics: Biosynthesis, Generation of Novel Compounds

The elucidation of the molecular machinery of antibiotic biosynthesis enabled technologies that can be used to optimize the secondary metabolites by genetic engineering are highlighted and some strategies are highlighted which allow the modification of secondary metabolites in ways that were hard to achieve using only synthetic chemistry approaches.

Polyketide Biosynthesis: Modular Polyketide Synthases

This review provides new perspectives on important biosynthetic mechanisms that contribute to the introduction of unique chemical functionality into these fascinating systems of polyketides.



Combinatorial biosynthesis in microorganisms as a route to new antimicrobial, antitumor and neuroregenerative drugs.

Many new tools for manipulating and studying the multifunctional PKSs have been developed including the development of Escherichia coli as a PKS expression last, which has resulted in faster ways of engineering PKS to produce new compounds for theDevelopment of chemotherapeutic agents from natural products.

Combinatorial biosynthesis of reduced polyketides

The bacterial multienzyme polyketide synthases produce a diverse array of products that have been developed into medicines, including antibiotics and anticancer agents, but key challenges remain before the potential of combinatorial biosynthesis can be fully realized.

Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel ‘ ‘ unnatural ’ ’ natural products

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New aminocoumarin antibiotics from genetically engineered Streptomyces strains.

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Rapid Engineering of the Geldanamycin Biosynthesis Pathway by Red/ET Recombination and Gene Complementation

Red/ET recombination in an Escherichia coli host has permitted rapid and more versatile engineering of geldanamycin biosynthetic genes in a complementation plasmid, which can then be readily transferred into the Streptomyces host from which the corresponding wild type gene has been removed.

Redesign, synthesis and functional expression of the 6-deoxyerythronolide B polyketide synthase gene cluster

This work synthesized the six-module DEBS gene cluster optimized for codon usage in E. coli, and cloned the three open reading frames into three compatible expression vectors that were compatible with polyketide production.

Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes

A generic approach to the design of synthetic PKS genes where facile cassette assembly and interchange of modules and domains are facilitated by a repeated set of flanking restriction sites, providing a truly combinatorial approach for the production of polyketides.

The biosynthesis of glycopeptide antibiotics—a model for complex, non-ribosomally synthesized, peptidic secondary metabolites

An overview of the current knowledge regarding biosynthetic glycopeptide assembly is provided and there has been considerable progress in elucidating the biosynthesis of glycopePTide antibiotics by combining molecular biology and analytical chemistry methods.

Combinatorial biosynthesis of novel antibiotics related to daptomycin

This study established a robust combinatorial biosynthesis platform to produce novel peptide antibiotics in sufficient quantities for antimicrobial screening and drug development.