The cationic peptide octaarginine (R8) is a prominent cell-penetrating peptide and has been extensively researched as a carrier of diverse cell-destined cargo. In this work, we describe the coassembly of R8 with small molecule thiazolyl benzenesulfonamide (TBS) derivatives. Physical complexation of R8 with three TBS derivatives across a range of weight ratios results in the formation of a distinctive set of nano- and microstructures. A detailed structural characterization of the R8:TBS-derivative coassemblies has been performed by a combination of FTIR, XRD, SEM, and DSC. The major functional groups that facilitate coassembly include sulfonamide SO and NH groups of the TBS derivatives, and the guanidinium of R8, via a combination of cation-�� and hydrogen-bonding interactions. The R8:4F-TBS coassembly displays singular topological features compared to R8:4Br-TBS and R8:4CH-TBS complexes. These differences are attributed to the changes in the preferred orientation of the guanidino groups of R8 with respect to the ��-surface of TBS derivatives. The modulation of forces of interaction across the R8:TBS-derivative coassemblies aligns with their respective thermal stabilities. The single-crystal structure of bare 4F-TBS has been subjected to Hirshfeld and 2D fingerprinting analysis and indicates notable variations from the crystal packing of the R8:4F-TBS coassembly. The structural differences among the R8:TBS-derivative coassemblies correlate with distinctive profiles of antibacterial activity in each case. The coassembled structures exert a variable extent of bacterial membrane disruption and damage based on the unique disposition of R8 and the potency of small molecule in each case. The aqueous suspension of R8:4F-TBS displays significant outer membrane disruption and bacterial killing compared with the other complexes. This work successfully demonstrates the hitherto unreported potential for coassembly of cell-penetrating peptides with other entities. The coassembly of R8 with small molecules highlights an attractive strategy for tuning the functional properties of each component.
