Highlights of Streptomyces genetics

Abstract

Sixty years ago, the actinomycetes, which include members of the genus Streptomyces, with their bacterial cellular dimensions but a mycelial growth habit like fungi, were generally regarded as a possible intermediate group, and virtually nothing was known about their genetics. We now know that they are bacteria, but with many original features. Their genome is linear with a unique mode of replication, not circular like those of nearly all other bacteria. They transfer their chromosome from donor to recipient by a conjugation mechanism, but this is radically different from the E. coli paradigm. They have twice as many genes as a typical rod-shaped bacterium like Escherichia coli or Bacillus subtilis, and the genome typically carries 20 or more gene clusters encoding the biosynthesis of antibiotics and other specialised metabolites, only a small proportion of which are expressed under typical laboratory screening conditions. This means that there is a vast number of potentially valuable compounds to be discovered when these 'sleeping' genes are activated. Streptomyces genetics has revolutionised natural product chemistry by facilitating the analysis of novel biosynthetic steps and has led to the ability to engineer novel biosynthetic pathways and hence 'unnatural natural products', with potential to generate lead compounds for use in the struggle to combat the rise of antimicrobial resistance.

Fig. 1

Scanning electron micrograph of a colony of Streptomyces lividans growing on an agar plate in the laboratory. At the edge of the colony, hyphae of the substrate mycelium are foraging for nutrients on the surface of the medium and burrowing into it, while in the central regions the aerial hyphae are beginning to produce spores. From Figure 6.01 of Hopwood (2007), reproduced by permission of Oxford University Press

Fig. 2

Electron micrographs of thin sections of Streptomyces coelicolor and Bacillus subtilis showing the very similar cellular architecture of these two prokaryotes. (V = vacuoles left when storage compounds in the germinating spore have disappeared; N = DNA of the genome – note the absence of a nuclear envelope separating it from the cytoplasm, M = mesosomes – membranous bodies carrying out the functions of eukaryotic mitochondria (these are also found in bacilli but not seen clearly in this section). From Figure 3.06 of Hopwood (2007), reproduced by permission of Oxford University Press

Fig. 3

Cultures of Streptomyces coelicolor making blue actinorhodin (top left), Streptomyces sp. AM-7161 making brown medermycin (top right) and a recombinant strain making purple mederhodin. Photograph courtesy of Helen Kieser

Fig. 4

a The assembly line model for the biosynthesis of erythromycin in Saccharopolyspora (formerly Streptomyces) erythrea. b, c Details of the domain structure of two of the polyketide synthase proteins. AT, acyl transferase; ACP, acyl carrier protein; KS, ketosynthase; KR, ketoreductase; DH, dehydratase; ER, enoyl reductase. The unshaded domain at the right end of protein 3 in a is the thioesterase. From Figure 8.11 of Hopwood (2007), reproduced by permission of Oxford University Press

Fig. 5

Circular representation of the Streptomyces coelicolor chromosome showing the telomere proteins as small blue circles and the centrally located origin of replication. The outer scale is numbered anticlockwise in megabases. The other circles show various features of the genome, circles 1 and 2 from the outside in representing all the genes on the two strands of the DNA. From Bentley et al. (2002)