We are facing a shortage of new antibiotics to fight against increasingly resistant bacteria. As an alternative to conventional small molecule antibiotics, antimicrobial polymers (AMPs) have great potential. These polymers contain cationic and hydrophobic groups and disrupt bacterial cell membranes through a combination of electrostatic and hydrophobic interactions. While most examples focus on ammonium-based cations, sulfonium groups are recently emerging to broaden the scope of polymeric therapeutics. Here, main-chain sulfonium polymers exhibit good antimicrobial activity. In contrast, the potential of side-chain sulfonium polymers remains less explored with structure–activity relationships still being limited. To address this limitation, we thoroughly investigated key factors influencing antimicrobial activity in side-chain sulfonium-based AMPs. For this, we combined sulfonium cations with different hydrophobic (aliphatic/aromatic) and hydrophilic polyethylene glycol (PEG) groups to create a library of polymers with comparable chain lengths. For all compositions, we additionally examined the position of cationic and hydrophobic groups on the polymer backbone, i.e. , we systematically compared same center and different center structures. Bactericidal tests against Gram-positive and Gram-negative bacteria suggest that same center polymers are more active than different center polymers of similar clog P . Ultimately, sulfonium-based AMPs show superior bactericidal activity and selectivity when compared to their quaternary ammonium cationic analogues.
