Marrying synthetic biology with synthetic chemistry provides a powerful approach toward natural product diversification, combining the best of both worlds: expediency and synthetic capability of biogenic pathways and chemical diversity enabled by organic synthesis. Biosynthetic pathway engineering can be employed to insert a chemically orthogonal tag into a complex natural scaffold affording the possibility of site-selective modification without employing protecting group strategies. Here we show that, by installing a sufficiently reactive handle (e.g., a C–Br bond) and developing compatible mild aqueous chemistries, synchronous biosynthesis of the tagged metabolite and its subsequent chemical modification in living culture can be achieved. This approach can potentially enable many new applications: for example, assay of directed evolution of enzymes catalyzing halo-metabolite biosynthesis in living cells or generating and following the fate of tagged metabolites and biomolecules in living systems. We report synthetic biological access to new-to-nature bromo-metabolites and the concomitant biorthogonal cross-coupling of halo-metabolites in living cultures.

Aqueous Sonogashira cross-coupling of unprotected bromotryptophan, tripeptides and a new to nature natural product (accessed through biosynthetic manipulation) is reported.

The blending of synthetic chemistry with biosynthetic processes provides a powerful approach to synthesis. Biosynthetic halogenation and synthetic cross‐coupling have great potential to be used together, for small molecule generation, access to natural product analogues and as a tool for chemical biology. However, to enable enhanced generality of this approach, further synthetic tools are needed. Though considerable research has been invested in the diversification of phenylalanine and tyrosine, functionalisation of tryptophans thorough cross‐coupling has been largely neglected. Tryptophan is a key residue in many biologically active natural products and peptides; in proteins it is key to fluorescence and dominates protein folding. To this end, we have explored the Heck cross‐coupling of halo‐indoles and halo‐tryptophans in water, showing broad reaction scope. We have demonstrated the ability to use this methodology in the functionalisation of a brominated antibiotic (bromo‐pacidamycin), as well as a marine sponge metabolite, barettin.

Herein, novel drug-eluting, bio-absorbable scaffold intended to cover piercing studs is introduced. This “biopierce” will stay in human tissue following piercing, and will slowly release an antimicrobial agent to prevent infection while the wound heals. Nearly 20% of all piercings lead to local infection. Therefore, it is imperative to develop alternative methods of piercing aftercare to prevent infection. Biopierces were made using mupirocin loaded poly-lactic-co-glycolic acid (PLGA) biomaterial ink, and a low-temperature 3D printing technique was used to fabricate the biopierces. Proton nuclear magnetic resonance (¹H NMR) spectroscopy was used to confirm the complete removal of the solvent, and liquid chromatography high-resolution mass spectrometry (LC-HRMS) was used to confirm the structural integrity of mupirocin and to quantify the amount of the released drug over time. The efficacy of the biopierces against Staphylococcus aureus, one of the most common piercing-site pathogens, was confirmed over two weeks using in vitro antimicrobial susceptibility testing.