SuperBola Cationic Biocides with an Extended Bolaamphiphilic Structure: How Much Is Too Much?

Cationic biocides have served as effective disinfectants for nearly a century; however, our reliance on a relatively narrow set of amphiphilic structures has led to increasing levels of bacterial resistance. Recent literature has indicated that bolaamphiphiles, biscationic species bearing a nonpolar linker, show promise as advantageous architectures that display excellent antibacterial potency, while showing diminished susceptibility to bacterial resistance mechanisms. Since extended bolaamphiphilic linkers have been employed in multiple compelling structures, but had not been investigated in a systematic way, we decided to investigate structure–activity relationships of “SuperBola” structures, specifically bearing simple hydrocarbon linkers ranging from 12 to 18 carbons. In assessing 36 novel structures featuring ammonium, imidazolium, and aminopyridinum headgroups, a surprisingly wide set of potent compounds was identified, and strong bioactivity (i.e., single-digit micromolar MIC values) corresponded to an ideal amphiphilic balance, which corresponded to a consensus cLogPo/w value of roughly 5, as indicated by SwissADME. Potent activity was identified across a range of Gram-positive, Gram-negative, and resistant bacterial strains.