Biocatalysis is constantly providing novel options for the synthesis of active pharmaceutical ingredients (APIs). In addition to drug development and manufacturing, biocatalysis also plays a role in drug discovery and can support many active ingredient syntheses at an early stage to build up entire scaffolds in a targeted and preparative manner. Recent progress in recruiting new enzymes by genome mining and screening or adapting their substrate, as well as product scope, by protein engineering has made biocatalysts a competitive tool applied in academic and industrial spheres. This is especially true for the advances in the field of nonribosomal peptide synthesis and enzyme cascades that are expanding the capabilities for the discovery and synthesis of new bioactive compounds via biotransformation. Here we highlight some of the most recent developments to add to the portfolio of biocatalysis with special relevance for the synthesis and late-stage functionalization of APIs, in order to bypass pure chemical processes.

Siderophores are small molecules secreted by microorganisms in order to scavenge iron from the environment. An example is the thiazoline-containing natural product massiliachelin, which is produced by Massilia sp. NR 4-1 under iron-deficient conditions. Based on experimental evidence and genome analysis, it was suspected that this bacterium synthesizes further iron-chelating molecules. After a thorough inspection of its metabolic profile, six previously overlooked compounds were isolated that were active in the chrome azurol S (CAS) assay. Mass spectrometric measurements and nuclear magnetic resonance spectroscopic analyses identified these compounds as possible biosynthetic intermediates or shunt products of massiliachelin. Their bioactivity was tested against one Gram-positive and three Gram-negative bacteria.

Four new phenolic siderophores were isolated from the actinomycete Nocardia altamirensis along with the known natural product amamistatin B and a putative biosynthetic shunt product. The structures of all compounds were elucidated through 1D and 2D NMR analyses as well as mass spectrometry. The iron-chelating properties of the retrieved metabolites were evaluated in a chrome azurol S assay.