Intracellular bacterial targeting by a thiazolyl benzenesulfonamide and octaarginine peptide complex

Abstract

A brominated thiazolyl benzenesulfonamide (BTB) derivative is conjugated with thecell-penetrating peptide octaarginine (R8) in an effort to construct innovative antibacterial products.The noncovalent complex of BTB and R8 is characterized by Fourier transform infrared (FTIR)spectroscopy, which indicates hydrogen bonding between the two constituents. Attachment of thepeptide moiety renders aqueous solubility to the hydrophobic benzenesulfonamide drug and bestows bactericidal activity. Confocal imaging in conjunction with dye probes shows successful clearance ofintracellular Staphylococcus aureusbacteria by the BTB-R8 complex. Scanning electron micrographsand studies with a set offluorescent dyes suggest active disruption of the bacterial cell membrane bythe BTB-R8 complex. In contrast, the complex of BTB with octalysine (K8) fails to causemembrane damage and displays a modest antibacterial effect. A complex of BTB with the water-soluble hydrophilic polymer poly(vinylpyrrolidone) (PVP) does not display any antibacterial effect,indicating the distinctive role of the cell-penetrating peptide (CPP) R8 in the cognate complex. Theleakage of the encapsulated dye from giant unilamellar vesicles upon interaction with the BTB-R8complex further highlights the membrane activity of the complex, which cannot be accomplished bybare sulfonamide alone. This work broadens the scope of use of CPPs with respect to eliciting antibacterial activity and potentiallyexpands the limited arsenal of membrane-targeting antibiotics.