Peripheral modification is often the main approach to optimize natural products for improved biological activity or desired physicochemical properties. This procedure inevitably increases molecular weight, often accompanied by undesired increased lipophilicity. Removing structural elements from natural products is not always tolerated. This is also the case for the antibiotic fidaxomicin (Fdx), where every structural component has been shown to be crucial for antibiotic activity. In this work, we demonstrate how the residue switching approach can maintain biological activity of Fdx derivatives by replacing the rhamnoside-dichlorohomoorsellinate moiety of Fdx with smaller, more polar building blocks. We used palladium-catalysed allylic substitution to selectively install N-nucleophiles on the core of Fdx. The new derivatives were designed to mimic the binding of Fdx to the bacterial RNA polymerase. Evaluation against Mycobacterium tuberculosis, Clostridioides difficile, and the Gram-negative model organism Caulobacter crescentus demonstrated that the newly introduced residues can restore antibiotic activity, which was further supported by on-target RNA polymerase assays. We combined the allylic substitution with an organocatalysed novioside acylation protocol to enable the functionalisation of two vectors on Fdx in one pot. This platform greatly expands the accessible chemical space for Fdx derivatives and enables the future development of systemic Fdx antibiotics.