Antibacterial and Antibiofilm Activity of Cationic Small Molecules with Spatial Positioning of Hydrophobicity: An in Vitro and in Vivo Evaluation

More than 80% of the bacterial infections
are associated with biofilm
formation. To combat infections, amphiphilic small molecules have
been developed as promising antibiofilm agents. However, cytotoxicity
of such molecules still remains a major problem. Herein we demonstrate
a concept in which antibacterial versus cytotoxic activities of cationic
small molecules are tuned by spatial positioning of hydrophobic moieties
while keeping positive charges constant. Compared to the molecules
with more pendent hydrophobicity from positive centers (MIC = 1–4
μg/mL and HC50 = 60–65 μg/mL), molecules
with more confined hydrophobicity between two centers show similar
antibacterial activity but significantly less toxicity toward human
erythrocytes (MIC = 1–4 μg/mL and HC50 = 805–1242
μg/mL). Notably, the optimized molecule is shown to be nontoxic
toward human cells (HEK 293) at a concentration at which it eradicates
established bacterial biofilms. The molecule is also shown to eradicate
preformed bacterial biofilm in vivo in a murine model
of superficial skin infection.