Exchanging a single atom in a molecule can significantly impact its biological and chemical characteristics. Systematic investigation on the effect of a single atom swap enables to understand the structure-activity relationship (SAR) of biologically active molecules in detail and allows precise structure-based design in a medicinal chemistry context. Selected examples from the field of drug development display the plethora of applications for single atom modifications and their beneficial effect on the stability (e.g. flurithromycin, CC-1065 analogue, 1 salvinorin A derivative), solubility (e.g. sotorasib), biological activity (e.g. vancomycin derivatives, 1 CC-1065 analogue), or synthetic complexity (e.g. salvinorin A derivative) (Fig. ). As single-atom exchanges can exert tremendous impact on the physicochemical properties of molecules, methods to enable precise, late-stage single atom molecular editing are highly sought-after. In this work we present our strategy for a formal single atom O-/S-exchange in the natural product antibiotic fidaxomicin (Fdx, 1) to overcome its acid lability with the ultimate goal to extend its application portfolio.