Antimicrobial Conjugated Oligoelectrolytes Containing Triphenylphosphonium Solubilizing Groups

Conjugated oligoelectrolytes (COEs) are an emerging class of amphiphilic antimicrobial compounds with a modular molecular framework suitable for simple chemical derivatization. Here, a series of COE derivatives with a stilbene‐conjugated segment and triphenylphosphonium (TPP) pendant groups was designed and synthesized to understand how lipophilic cationic groups impact antimicrobial activity. In vitro evaluations against ESKAPE pathogens showed broad‐spectrum activity towards multi‐drug resistant (MDR) bacteria and mycobacteria, with TPP groups enhancing antimicrobial activity towards clinically relevant Gram‐negative strains compared to their ammonium analogues. We studied the interactions of DM6P, the most active TPP‐COE compound, with various membrane assays. Treatment of bacterial cells with DM6P showed enhanced permeability of cell membranes without inducing the development of significant bacterial resistance. Moreover, DM6P eliminated 99.99 % of methicillin‐resistant Staphyloccocus aureus (MRSA) in an in vivo wound model. These results represent a promising chemical strategy for increasing the activity spectrum of membrane‐active COE antibiotics to tackle challenging drug‐resistant targets. PPh3 helps protect against pathogens: Conjugated oligoelectrolytes are a modular molecular platform for the design of novel antimicrobial agents. Substituting terminal alkylammonium cationic groups with more lipophilic triphenylphosphonium counterparts enabled bactericidal activity towards ESKAPE pathogens and clinically relevant mycobacteria. In vivo efficacy was verified in a murine wound model, at clinically relevant dosages.