Engineering cyanobacteria and their toxin biosynthesis pathways for unnatural production

The past two decades has witnessed major advances in our understanding of natural product biosynthesis, including the genetic basis for toxin production by a number of groups of bacteria and fungi. Cyanobacteria produce an unparalleled array of bioactive secondary metabolites, including alkaloids, polyketides and non-ribosomal peptides, some of which are potent toxins. Most cyanobacterial genera have either been shown to produce non-ribosomal peptides or have them encoded within their genomes. Early work on the genetics of cyanobacterial toxicity led to the discovery of one of the first examples of hybrid peptide-polyketide synthetases. This enzyme complex directed the production of the cyclic heptapeptide, microcystin, while a homologous gene cluster responsible for the synthesis of the pentapeptide nodularin, provided evidence of genetic recombination and possible gene transfer. More recently, hybrid peptide and polyketide synthetic pathways have been implicated in the production of the alkaloid cylindrospermopsin, and this information, in-turn, has provided the first evidence of genes involved in bacterial non-terpene alkaloid biosynthesis. Candidate gene loci involved in saxitoxin production have been identified in diverse cyanobacteria and algae. Genomic information has also indicated the cellular regulators of toxin production, as well as associated transport mechanisms. Exploiting what we refer to as toxins, such as microcystin, is the beginning of the unlimited potential in natural product biosynthetic engineering for the creation of unnatural antibiotics, antivirals, and immunosuppressants. Current directions in drug design and sustainable production, bioprospecting, and ethnopharmacology will be discussed as outcomes of this work.