Genetics of antibiotic production

Hopwood, David A.; Merrick, Mike

doi:10.1128/br.41.3.595-635.1977

Cited by 79 publications

(9 citation statements)

References 213 publications

(2 reference statements)

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“…In particular, the bacterium's natural capacity to produce nonribosomal peptides would indicate that it would be suitable as a heterologous host for this natural product class. 7,187,188 In addition, the organism's rapid growth rate, capability to become naturally competent, and thorough characterization offers a range of available recombinant techniques to aid a particular heterologous biosynthetic effort.…”

Section: Bacillus Subtilismentioning

confidence: 99%

Methods and options for the heterologous production of complex natural products

et al. 2011

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Section: Bacillus Subtilismentioning

confidence: 99%

Methods and options for the heterologous production of complex natural products

et al. 2011

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“…Over and above this, probably at least several hundred genes affect the amount of antibiotic produced under a given set of environmental conditions. Thus antibiotic titre in a fermentor is a classical continuously variable character that would require a painstaking biometrical analysis to describe (Hopwood & Merrick 1977). This is why, apart from the special cases of significant metabolic 'bottlenecks' discussed above, antibiotic 'yield' is not an ideal situation for the kind of single gene cloning solution that would be suitable for improving the production of a useful industrial enzyme or mammalian hormone.…”

Section: R 119 ] (C) Understanding and Manipulating The Regulation Of Antibiotic Biosynthesismentioning

confidence: 99%

Antibiotics: opportunities for genetic manipulation

1989

Phil. Trans. R. Soc. Lond. B

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New antibiotics can still be discovered by the development of novel screening procedures. Notable successes over the last few years include the monobactams, beta-lactamase inhibitors (clavulanic acid) and new glycopeptides in the antibacterial field; antiparasitic agents such as avermectins; and herbicidal antibiotics like bialaphos. In the future we can expect the engineering of genes from 'difficult' pathogens, including mycobacteria and fungi, and cancer cells, to provide increasingly useful in vitro targets for the screening of antibiotics that can kill pathogens and tumours. There will also be a greater awareness of the need to reveal the full potential for antibiotic production on the part of microorganisms by the physiological and/or genetic awakening of 'silent' genes. Nevertheless, the supply of natural antibiotics for direct use or chemical modification is not infinite and there will be increasing scope for widening the range of available antibiotics by genetic engineering. 'Hybrid' antibiotics have been shown to be generated by the transfer of genes on suitable vectors between strains producing chemically related compounds. More exciting is the possibility of generating novelty by the genetic engineering of the synthases that determine the basic structure of antibiotics belonging to such classes as the beta-lactams and polyketides. Research in this area will certainly yield knowledge of considerable scientific interest and probably also of potential applicability. In the improvement of antibiotic titre in actinomycetes, protoplast fusion between divergent selection lines has taken a place alongside random mutation and screening. In some cases the cloning of genes controlling metabolic 'bottlenecks' in fungi and actinomycetes will give an immediate benefit in the conversion of accumulated biosynthetic intermediates to the desired end product. However, the main impact of genetic engineering in titre improvement will probably come only after a further use of this technology to understand and manipulate the regulation of antibiotic biosynthesis as a facet of the general challenge of understanding differential gene expression. Streptomyces offers a particularly fertile field for such research, following the isolation of DNA segments that carry groups of closely linked operons for the biosynthesis of and resistance to particular antibiotics, and of genes with pleiotropic effects on morphological differentiation and secondary metabolite formation.

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“…A more certain and more rational application of recombination to the generation of new antibiotics is the transfer of genes between strains or species making different members of the same chemical family of antibiotics, to produce a strain making a 'hybrid' molecule. There is considerable evidence that the enzymes of secondary metabolism are less specific than those of prim ary biosynthetic pathways (Hopwood & Merrick 1977) and a case in point is the production of new antibiotics (usually aminoglycosides in present examples) by the technique of ' mutational biosynthesis' (Nagaoka & Demain 1975) or 'mutasynthesis' (Rinehart 1977;Shier et al 1969). Mutants blocked in the synthesis of the aminocyclitol moiety of such antibiotics are fed with analogues of the normal moiety, which are accepted by the biosynthetic enzymes, to produce novel aminoglycoside antibiotics.…”

Section: (C) Genetic Approachesmentioning

confidence: 99%

“…W hat ever the mechanism, however, this example is interesting in emphasizing the validity of a recombinational approach to the discovery of new antibiotics. It also emphasizes the need for information on the number and organization of structural genes for antibiotic biosynthesis, a subject on which very little information still exists, if new hybrid antibiotics are to be con structed rationally and if the origin of putative chemical hybrids is to be correctly interpreted (Hopwood & Merrick 1977;Hopwood 1978;Chater 1979).…”

Section: (C) Genetic Approachesmentioning

confidence: 99%

“…It is evident that considerable scope exists for the application of genetic techniques in new ways to both the qualitative and the quantitative aspects of antibiotic production. Although members of each of the main groups of antibiotic producing microorganisms have natural systems of genetic recombination, these are rarely ideal for practical purposes, usually because their frequency is either uncharacterized or low compared with that of asexual reproduction in industrially relevant strains (Hopwood & Merrick 1977). Moreover, they are largely confined, by definition, to gene transfers between members of the same species.…”

Section: N Ew Techniques For Genetic Manipulationmentioning

confidence: 99%

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Fresh approaches to antibiotic production

Hopwood

Chater

1980

Phil. Trans. R. Soc. Lond. B

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New antibiotics are needed, (a) to control diseases that are refractory to existing ones either because of intrinsic or acquired drug resistance of the pathogen or because inhibition of the disease is difficult, at present, without damaging the host (fungal and viral diseases, and tumours), (b) for the control of plant pathogens and of invertebrates such as helminths, insects, etc., and (c) for growth promotion in intensive farming. Numerous new antibiotics are still being obtained from wild microbes, especially actinomycetes. Chemical modification of existing compounds has also had notable success. Here we explore the uses, actual and potential, of genetics to generate new antibiotics and to satisfy the ever-present need to increase yield. Yield improvement has depended in the past on mutation and selection, combined with optimization of fermentation conditions. Progress would be greatly accelerated by screening random recombinants between divergent high-yielding strains. Strain improvement may also be possible by the introduction of extra copies of genes of which the products are rate-limiting, or of genes conferring beneficial growth characteristics. Although new antibiotics can be generated by mutation, either through disturbing known biosyntheses or by activating 'silent' genes, we see more promise in interspecific recombination between strains producing different secondary metabolities, generating producers of 'hybrid' antibiotics. As with proposals for yield improvement, there are two major strategies for obtaining interesting recombinants of this kind: random recombination between appropriate strains, or the deliberate movement of particular biosynthetic abilities between strains. The development of protoplast technology in actinomycetes, fungi and bacilli has been instrumental in bringing these idealized strategies to the horizon. Protoplasts of the same or different species can be induced to fuse by polyethylene glycol. At least in intraspecific fusion of streptomyces, random and high frequency recombination follows. Protoplasts can also be used as recipients for isolated DNA, again in the presence of polyethylene glycol, so that the deliberate introduction of particular genes into production strains can be realistically envisaged. Various kinds of DNA cloning vectors are being developed to this end. Gene cloning techniques also offer rich possibilities for the analysis of the genetic control of antibiotic biosynthesis, knowledge of which is, at present, minimal. The information that should soon accrue can be expected to have profound effects on the application of genetics to industrial microbiology.

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Genetics of antibiotic production

Cited by 79 publications

References 213 publications

Methods and options for the heterologous production of complex natural products

Methods and options for the heterologous production of complex natural products

Antibiotics: opportunities for genetic manipulation

Fresh approaches to antibiotic production

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