Introduction of a Non-Natural Amino Acid into a Nonribosomal Peptide Antibiotic by Modification of Adenylation Domain Specificity

Calcium‐dependent antibiotics (CDA) are cyclic lipopeptides assembled by nonribosomal peptide synthetase (NRPS) enzymes. Active site modification of the 3‐methyl glutamate activating adenylation (A) domain of the CDA NRPS enables the incorporation of synthetic 3‐methyl glutamine into CDA. This provides the first example of how A‐domains can be engineered to introduce synthetic “non‐natural” amino acids into nonribosomal peptides.