Prospects for generating new antibiotics.

A plethora of human pathogens are now resistant to all clinically significant antibiotics causing a crisis, in the treatment and management of infectious diseases, but also presenting a clear danger to future public health. If drug resistance is going to be tackled successfully, new antibiotics must be continually developed to counteract the processes of evolution and natural selection in these populations of pathogens. Despite the introduction of powerful new technologies such as high throughput screening platforms and combinatorial chemistry, natural products still offer structural diversity worthy of screening for biological activity. Functional genomics can revolutionise rational drug design providing new targets for antimicrobial drug discovery. The clusters of genes, encoding enzymes that form bio-synthetic pathways leading to the synthesis of many natural products including polyketides and non-ribosomal peptides, are amenable to modern genetic engineering. Repositioning, deleting and replacing genes in these biosynthetic clusters has resulted in the synthesis of many 'un-natural' natural products. This review examines the engineering of proteins involved in chain initiation on polyketide synthases culminating in the production at high yield of a biologically active erythromycin derivative.