They do have great advantages, although a direct comparison of the success and failure of synthetic as against natural product libraries is unfair. Microbial natural products have evolved over millennia to interact with biological molecules, whereas the synthetic chemical libraries used in antibiotic drug-discovery screens were generally developed with a focus on eukaryotic drug-discovery campaigns, as noted earlier. Efforts to develop physical-property rules for antibiotics and to incorporate natural-product-like chemical complexity in libraries of synthetic chemicals will no doubt improve success in identifying new synthetic antibiotic leads.
Ironically, at the same time that the pharmaceutical industry was abandoning natural-product libraries, university researchers were making remarkable advances in understanding the molecular details of natural-product biosynthesis by bacteria. Many bacteria, especially the actinomycete group of common environmental bacteria, are prodigious producers of natural products. These are termed secondary metabolites to contrast with molecules of primary metabolism, such as carbohydrates, amino acids and so on. Secondary metabolites range in molecular weight from around 100 daltons (Da) to up to 5,000 Da and they have diverse biological activities, including induction of cell death (antibiotics such as tetracycline, vancomycin and daptomycin, and anticancer agents such as adriamycin), iron sequestration (for example, enterobactin), facilitation of cell-cell communication (γ-butyrolactones), protection from oxidizing agents (phenazines), and a host of others.
The bacterial natural products that are most important as antibiotics include polyketides, such as the macrolides and tetracyclines, and non-ribosomal peptides - that is, peptides that are not synthesized on ribosomes - which include β-lactams and glycopeptides such as vancomycin. These are produced in the cell in assembly-line fashion on large dedicated enzyme platforms called, respectively, polyketide synthases and non-ribosomal peptide synthetases. Following assembly the compounds are then 'decorated' by a series of modifying enzymes, such as glycosyltransferases. The end result is a molecule of often complex structure, with multiple chiral centers and functional groups such as sugars, halogens, sulfates, acyl groups and others.
In general, bacterial genes that encode the production of natural products are clustered together in the genome, greatly facilitating analysis and prediction of biosynthetic pathways and structures. Indeed, several software packages (for example, NP. searcher) have been developed based on rules-based understanding of natural-product biosynthesis. The availability of cheap, rapid genome sequencing means that time-consuming construction and screening of gene libraries for natural-product clusters can now be bypassed. Genome sequencing has also revealed a hitherto unrealized richness in the quantity and variability of natural-product biosynthetic clusters. Sequenced genomes of bacteria of the actinomycetes class reveal 20 to 30 biosynthetic clusters in each organism. Furthermore, natural-product producing bacteria from non-soil environments are being investigated and these have already resulted in new chemical matter, suggesting that there is a fantastic wealth of untapped chemical diversity waiting to be discovered. Perhaps some of this diversity will include new antibiotic chemical scaffolds.
We are in a remarkably productive time for natural-product research that is serving to reinvigorate interest in this sector. At the same time, the application of synthetic biology approaches to this field could serve to improve issues of yield and expand chemical diversity.