Chapter 2. From microbial products to novel drugs that target a multitude of disease indications

Abstract

More than 20,000 bioactive, so-called microbial secondary metabolites are known. In nature, they can play many different roles as antibiotics, toxins, ionophores, bioregulators, and in intra- and interspecific signaling. Their most versatile producers are differentiating filamentous fungi and actinomycetes, followed by other bacteria such as Bacillus, Pseudomonas, Myxobacteria, and Cyanobacteria. From a biotechnological point of view, bioactive metabolites have been mainly studied as potential anti-infectives (antibacterials, antifungals, antivirals, and antiparasitics). Many of them, originally discovered for their antibiotic activity, were developed further to become leading anticancer drugs, immunosuppressive agents for organ transplantation, and successful pharmaceuticals targeting metabolic and cardiovascular diseases. Old and novel antitumor antibiotics can be divided into two groups spanning diverse chemical classes: those causing some damage to the DNA such as Mitomycins (quinones), Bleomycins (glycopeptides), Actinomycins (peptides), Anthracyclines (aromatic polyketides), Pentostatin (nucleoside), Enediynes (polyketides), and Rebeccamycin derivatives (indolocarbazole glycosides)-all produced by Streptomyces strains or related genera; and the group of tubulin-targeting molecules such as plant/fungal Taxanes (terpenes), myxobacterial Epothilones (macrocyclic polyketides), and the revisited Cryptophycins (peptolides) produced by cyanobacteria. Immunosuppressive agents used in clinical practice include Cyclosporin A (cyclopeptide) and an ester of Mycophenolic acid (small aromatic polyketide), both produced by fungi, and two streptomycete macrocyclic polyketides, Sirolimus (rapamycin) and Tacrolimus (FK506). Statins include a group of fungal polyketides (Compactin or Mevastatin, Lovastatin) and their derivatives, which specifically inhibit cholesterologenesis in liver, and represent the best-selling drugs. They have been used to prevent cardiovascular diseases.