Molecular engineering approaches to peptide, polyketide and other antibiotics

Abstract

Molecular engineering approaches to producing new antibiotics have been in development for about 25 years. Advances in cloning and analysis of antibiotic gene clusters, engineering biosynthetic pathways in Escherichia coli, transfer of engineered pathways from E. coli into Streptomyces expression hosts, and stable maintenance and expression of cloned genes have streamlined the process in recent years. Advances in understanding mechanisms and substrate specificities during assembly by polyketide synthases, nonribosomal peptide synthetases, glycosyltransferases and other enzymes have made molecular engineering design and outcomes more predictable. Complex molecular scaffolds not amenable to synthesis by medicinal chemistry (for example, vancomycin (Vancocin), daptomycin (Cubicin) and erythromycin) are now tractable by molecular engineering. Medicinal chemistry can further embellish the properties of engineered antibiotics, making the two disciplines complementary.