Engineering non-ribosomal peptide synthesis: tuning the antibiotics engine of the microbial world

Non-Ribosomal Peptide Synthetases produce chemically diverse peptides in nature, many of which have antimicrobial properties, providing an opportunity to use synthetic biology to fine tune them for pharmaceutical applications. Major challenges remain with total and semi-synthesis of these complex peptides with specific bioengineering methodologies being developed to increase low yields and enhance bioactivity. Here we review major advances in engineering non-ribosomal peptides with a focus on improvements made to achieve better yield and bioactivity. This can be achieved through: engineering precursor metabolites, altering metabolic flux, introducing strong promoters and regulators, and redirecting metabolism to biosynthetic gene clusters which can then be expressed natively or heterologously. We also review glycopeptide antibiotics as a promising opportunity for engineering through synthetic biology for the biosynthesis of novel non-ribosomal peptides.