Coassembly of Cell-Penetrating Peptide Octaarginine with Acetazolamide: Emergent Interactions with <i>E. coli</i>

The investigation of established pharmaceutical agents for recalibrating usage strongly supplements new drug development. In this work, we have prepared coassembled complexes of acetazolamide (AZM) with the cationic peptide octaarginine (R8) in an attempt to enhance its potency and scope of use. R8 and AZM in different weight ratios coassemble into remarkable nano- and microstructures such as ribbons, sheets, and stick-like structures. A combination of FTIR, XRD, SEM, and DSC has been used to characterize the R8:AZM coassemblies. The sulfonamide SO₂ and NH₂ groups of AZM are associated with the guanidinium amine, free amine, and terminal carbonyl groups of R8 resulting in distinctive topologies. Treatment of <i>Escherichia coli</i> with the complexes results in a distinctive pattern of membrane disruption and pore formation. The R8:AZM coassemblies inhibit carbonic anhydrase and <i>E. coli</i> growth with greater efficiency compared to bare AZM. The 1:5 <i>w</i>/<i>w</i> complex leads to pronounced outer and inner membrane rupture and significantly restricts glucose uptake by <i>E. coli</i>. The ability of R8 and AZM to coassemble into a distinctive set of structures based solely on differences in their relative proportions and their engagement with <i>E. coli</i> as more than the sum of their parts are novel facets of R8 and AZM behavior and underscore a straightforward and elegant approach for enhancing the scope of use of small molecule drugs.