The introduction of backbone aromatics into a biologically active cyclic peptide has the potential to be a relatively straightforward way to improve membrane permeability. However, as demonstrated here, very subtle changes to the nature of the aromatic group can have large impacts on either activity or permeability. Nonetheless, we also show that the use of a pyridine was able to maintain both in the case of Sanguinamide A. However, for other cyclic peptides, it is likely that multiple variants need to be explored to arrive at one that has the desired combination of effects.