PEGylated Bis-Quaternary Triphenyl-Phosphonium Tosylate Allows for Balanced Antibacterial Activity and Cytotoxicity

Quaternary triphenylphosphonium compounds (TPP⁺) have been widely recognized as an important antimicrobial because of their fast antimicrobial speed and broad antimicrobial spectrum. However, small-molecule TPP⁺ compounds have the defects of toxicity, which is the key factor that limits their practical applications. Here, two mono- and one bis-quaternary phosphonium tosylate compounds with different lengths of oligo(ethylene glycol) (OEG) chains and TPP⁺ as the active moiety were synthesized. Bis-TPP⁺ have a short OEG chain coupling two TPP⁺ at both ends, while mono-TPP⁺ attaches the OEG chain at one end in one molecule. In vitro antibacterial activities were evaluated against both Gram-positive as well as Gram-negative bacteria in terms of the inhibition zone (ZOI) and minimum inhibitory concentration (MIC). To investigate the antibacterial mechanism, β-galactosidase activity was monitored for measuring the degree of membrane permeability correlated to the abilities to disrupt the membranes of bacteria. Moreover, their structure-antibacterial activity and structure-cytotoxicity relationships were further analyzed. The results indicated that bis-TPP⁺ synthesized can reach the sterilization rate 90% or more against Escherichia coli and Staphylococcus aureus at MICs of 3.1 and 1.5 mg/mL, respectively, and meanwhile, the cell proliferation can reach more than 80%. This paper represents an excellent approach for development of bis-TPP⁺ bactericidal molecules that would achieve an optimal balance between antimicrobial activity and cytotoxicity.