Polyketide Synthase Engineering Toward Improved Antibiotics

Abstract

The steady rise of drug‐resistant bacteria coupled with decreasing numbers of viable therapeutics in the pharmaceutical pipeline underscores the need for novel strategies focused on rational exploration of chemical space to design and identify the next generation of antibiotics. Polyketides and non‐ribosomal peptides make up an enormous class of natural products whose unique biosynthetic assemblies provide great potential for engineered product variation in well‐defined chemical scaffolds. Unfortunately, most attempts to generate new biologically active analogs of these molecules have suffered from poor yields largely due to inherent specificity within the enzymes responsible for their production. Using an array of chemical and biological tools, our research focuses on understanding recognition motifs leading to this selectivity to potentially improve engineering efforts at both the genetic and molecular levels. If successful, this work will permit access to a wide‐variety of important compounds based on well‐studied, natural frameworks.