Antibiotics: opportunities for genetic manipulation

Abstract

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.

Analysis of coenzyme A activated compounds in actinomycetes

“…These organisms have been widely studied because of their remarkable impact on mankind, either as extremely dangerous pathogens, such as Mycobacterium tuberculosis , Mycobacterium leprae and Corynebacterium diphtheriae or, in the other extreme, as very useful sources of bioactive metabolites (Hopwood 1989; Krämer 1994). Both, fatty acid synthases and polyketide synthases use a wide range of acyl-CoA esters as substrate, or substrate precursors, for fatty acids or polyketide biosynthesis.…”

Characterization of FabG and FabI of the Streptomyces coelicolor Dissociated Fatty Acid Synthase

“…In streptomycetes, fabH, fabC (encoding the ACP), fabF, and fabD are clustered together as an operon. [2] Streptomycetes also produce a vast array of biologically active secondary metabolites widely used in human health, such as for antibacterial, immunosuppressant, anticancer, and antimalarial purposes, [3] and in a number of cases, these natural products use fatty acids as a building block. These fatty acids often differ in chain length or extent of branching from those made by the primary metabolic type II FAS (e.g., daptomycin, frenolicin, R1128, tunicamycin, and undecylprodiginine).…”

Knowns and unknowns of membrane lipid synthesis in streptomycetes

“…They form part of the class Actinobacteria, within the high G+C Gram positive bacteria. Their huge repertoire of diverse secondary metabolites has been exploited for biomedical purposes, and in addition to antibiotics, some of their natural products have found use as antifungic, antiparasitic, immunosupressant and antitumoral agents [1]. The life cycle of Streptomyces involves a complex morphological differentiation program akin to that of filamentous fungi, growing from a spore into a vegetative mycelium composed of branching hyphae.…”