Triscationic bolaamphiphilic QACs - optimizing antibacterial therapeutic indices.

Due to the relentless advance of bacterial resistance mechanisms, there exists an urgent need to develop novel surface disinfectants that eradicate a wide range of pathogenic bacteria. Our efforts in this arena have focused on optimization of potency, resistance-to-resistance, and safety. Herein, we report the efficient and modular construction of a series of triscationic quaternary ammonium compounds with a bolaamphiphilic architecture, based on a versatile phloroglucinol core where the cationic residues are either quaternized nitrogen atoms or imidazolium residues. A broad subset of the 28 prepared structures boast single-digit micromolar activity against a panel of eight bacteria that represent Gram-positive, Gram-negative, and resistant strains. Importantly, we have identified structure-activity relationships that highlight a set of four compounds (PHL-6,8, PHL-8,6, PHL-4-imid-8, and PHL-6-imid-6) that have MIC values generally ≤2 μM, as well as therapeutic indices (using red blood cell lysis as a proxy) of 32-250. Interestingly, a series of compounds with a single additional carbon per side chain shows marginally better potency (average MIC = 1 μM) but a significant jump in eukaryotic toxicity, dropping TI levels significantly. These observations reinforce the importance of amphiphilic balance in the development of disinfectant structures.