Recombinant microorganisms for industrial production of antibiotics

Abstract

The enhancement of industrial antibiotic yield has been achieved through technological innovations and traditional strain improvement programs based on random mutation and screening. The development of recombinant DNA techniques and their application to antibiotic producing microorganisms has allowed yield increments and the design of biosynthetic pathways giving rise to new antibiotics. Genetic manipulations of the cephalosporin producing fungus Cephalosporium acremonium have included yield improvements, accomplished increasing biosynthetic gene dosage or enhancing oxygen uptake, and new biosynthetic capacities as 7‐aminocephalosporanic acid (7‐ACA) or penicillin G production. Similarly, in Penicillium chrysogenum, the industrial penicillin producing fungus, heterologous expression of cephalosporin biosynthetic genes has led to the biosynthesis of adipyl‐7‐aminodeacetoxycephalosporanic acid (adipyl‐7‐ADCA) and adipyl‐7‐ACA, compounds that can be transformed into the economically relevant 7‐ADCA and 7‐ACA intermediates. Escherichia coli expression of the genes encoding D‐amino acid oxidase and cephalosporin acylase activities has simplified the bioconversion of cephalosporin C into 7‐ACA, eliminating the use of organic solvents. The genetic manipulation of antibiotic producing actinomycetes has allowed productivity increments and the development of new hybrid antibiotics. A legal framework has been developed for the confined manipulation of genetically modified organisms. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 216–226, 1997.

Regulation and compartmentalization of β‐lactam biosynthesis

“…The DAOC synthase of Streptomyces clavuligerus has been crystallized (Öster et al. , 2006) and the gene cefE has been introduced into P. chrysogenum , leading to the production of adipyl‐7‐aminodeacetoxycephalosporanic acid (ad‐7‐ADCA) and adipyl‐7‐ aminocephalosporanic acid (ad‐7‐ACA), (reviewed in Díez et al. , 1997).…”

Genetic improvement of processes yielding microbial products

“…The application of recombinant DNA technology to the production of secondary metabolites has been of great interest (Baltz & Hosted, 1996; Diez et al , 1997). The tools of the recombinant geneticist for increasing the titers of secondary metabolites have included: (i) transposition mutagenesis, (ii) targeted deletions and duplications by genetic engineering and (iii) genetic recombination by protoplast fusion (Baltz, 2003).…”

Strain improvement for cephalosporin production by Acremonium chrysogenum using geneticin as a suitable transformation marker

“…(1)(2)(3)(4)(5), from 5 C1 transformants (6-10), and from pASG418 (P), but not from the parental strains (B1 and C1). In this way, geneticin resistance can be used as primary marker for routine transformation experiments or as secondary marker in recombinant species where other resistances have been employed for primary selection.…”

“…The development of recombinant DNA techniques over the last 20 years for this filamentous fungus has allowed yield increments and the design of new biosynthetic pathways [1]. For many years genetic manipulation of industrial microorganisms was limited to improvement programs based on random mutation and selection, and even today these techniques are indispensable tools for the development of complex processes in which there is little background molecular knowledge.…”