Strategies for the Design and Discovery of Novel Antibiotics using Genetic Engineering and Genome Mining
José A. Salas
Departamento de Biología Funcional and Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006, Oviedo, Spain.
Most bioactive natural products currently known are synthesized by members of the Actinomycetales order. The development of genetic engineering provides novel genetic tools for the modification of known antibiotics and other bioactive compounds to generate derivatives with improved therapeutic properties. This new technology, named combinatorial biosynthesis, is able of introducing structural modifications in bioactive compounds not easily accessible by chemical means. Furthermore, progress in genome sequencing in this group of microorganisms shows that actinomycetes have a greater potential of synthesizing bioactive compounds than was anticipated. Each genome sequenced shows the presence of 18–37 gene clusters potentially directing the biosynthesis of bioactive compounds that have not been previously identified. Novel strategies are being developed to activate these cryptic or silent gene clusters in these microorganisms, allowing the identification of novel potentially bioactive compounds. This chapter will revise the state of the art in this field of research.