Coassembly of Cell-Penetrating\nPeptide Octaarginine\nwith Acetazolamide: Emergent Interactions with E. coli

The investigation of established pharmaceutical agents\nfor recalibrating\nusage strongly supplements new drug development. In this work, we\nhave prepared coassembled complexes of acetazolamide (AZM) with the\ncationic peptide octaarginine (R8) in an attempt to enhance its potency\nand scope of use. R8 and AZM in different weight ratios coassemble\ninto remarkable nano- and microstructures such as ribbons, sheets,\nand stick-like structures. A combination of FTIR, XRD, SEM, and DSC\nhas been used to characterize the R8:AZM coassemblies. The sulfonamide\nSO<sub>2</sub> and NH<sub>2</sub> groups of AZM are associated with\nthe guanidinium amine, free amine, and terminal carbonyl groups of\nR8 resulting in distinctive topologies. Treatment of Escherichia coli with the complexes results in a\ndistinctive pattern of membrane disruption and pore formation. The\nR8:AZM coassemblies inhibit carbonic anhydrase and E. coli growth with greater efficiency compared to\nbare AZM. The 1:5 <i>w</i>/<i>w</i> complex leads\nto pronounced outer and inner membrane rupture and significantly restricts\nglucose uptake by E. coli. The ability\nof R8 and AZM to coassemble into a distinctive set of structures based\nsolely on differences in their relative proportions and their engagement\nwith E. coli as more than the sum of\ntheir parts are novel facets of R8 and AZM behavior and underscore\na straightforward and elegant approach for enhancing the scope of\nuse of small molecule drugs.