Chapter 14 : Antibiotic Biosynthesis: Principles

Colorful antibiotics from streptomycetes. (From Sir David Hopwood, John Innes Centre, Norwich, United Kingdom, used with permission.)

Frequency of discovery of new antibiotics as a function of the total antibiotics discovered. Stt, streptothricin; Sm, streptomycin; Tet, tetracycline, Act, actinomycin; Van, vancomycin; Ery, erythromycin; Dap, daptomycin. (Reprinted from Baltz [2007] with permission.)

(a) Five antibiotics known to be produced by S. griseus—the aminoglycoside streptomycin and three polyketides: daunomycin, fredericamycin A, chromomycin A3, and a hybrid nonribosomal peptide-polyketide tetramate macrolactam. (b) Three antibiotics from S. coelicolor: actinorhodin, undecylprodigiosin, and Ca-dependent antibiotic.

Bioinformatic analysis of the seven chromosomes of A. fumigatus indicates 14 gene clusters for nonribosomal peptides or hybrids with polyketides (Hoffmeister and Keller, 2007). Four known metabolites are indicated here.

The streptomycete lantipeptide SapB is a developmental morphogen and has no antibiotic activity.

Correlation of bacterial genome size and secondary metabolite production. Donadio et al. (2007) suggested that genomes of ≤3 megabases of DNA would have little capacity for polyketides or nonribosomal peptides beyond siderophores needed for import of iron. It remains to be seen if the correlation holds when tens of thousands of additional bacterial genomes are curated. TMS, thiotemplate modular systems. (Adapted from Donadio et al. [2007] with permission.)

Novel natural product scaffolds from environmental DNA samples from uncultured organisms. The gene clusters were expressed in heterologous hosts to allow compound production and identification (Bauer et al., 2010; Biggens et al., 2012; Kallifidas et al., 2012).

Regulatory gene circuitry in S. griseus: action of butyrolactone quorum inducer via a series of positive and negative regulators to control synthesis of the buytrolactone and the steps for positive regulation (red arrow) for expression of the streptomycin biosynthetic gene cluster for production and secretion of the aminoglycoside antibiotic.

Three oxidation states at C6 of the butanolide scaffold are recognized by cognate receptors, FarA, ArpA, and BarA, in different streptomycetes. (Reprinted from Walsh [2003] with permission.)

Biosynthesis of 6α- and 6β-hydroxybutanolide diastereomers from DHAP and 3-ketoacyl coenzyme A by AfsA.

Three different structural platforms for quorum sensors: butyrolactones in different streptomycetes, acylhomoserine lactones in Gram-negative organisms, and peptidylthiolactones in strains of staphylococci. Different molecular scaffolds enable specific instructions in a sea of complex molecules.

Formation of the 3-ketoacylhomoserine lactone quorum sensors from SAM and the corresponding acyl-S-ACPs.