The　excessive　use　of　quaternary　ammonium　compounds　(QACs)　following　the　COVID-19　pandemic　has　raised　substantial　concerns　regarding　their　biosafety.　Overuse　of　QACs　has　been　associated　with　chronic　biological　adverse　effects,　including　genotoxicity　or　carcinogenicity.　In　particular,　inadvertent　intravascular　administration　or　oral　ingestion　of　QACs　can　lead　to　fatal　acute　toxicity.　To　enhance　the　biosafety　and　antimicrobial　efficacy　of　QACs,　this　study　reports　a　new　series　of　QACs,　termed　as　PACs,　with　the　alkyl　chain　of　benzalkonium　substituted　by　a　phthalocyanine　moiety.　Firstly,　the　rigid　phthalocyanine　moiety　enhances　the　selectivity　of　QACs　to　bacteria　over　human　cells　and　reduces　alkyl　chain＇s　entropic　penalty　of　binding　to　bacterial　membranes.　Furthermore,　phthalocyanine　neutralizes　hemolysis　and　cytotoxicity　of　QACs　by　binding　with　albumin　in　plasma.　Our　experimental　results　demonstrate　that　PACs　inherit　the　optical　properties　of　phthalocyanine　and　validate　the　broad-spectrum　antibacterial　activity　of　PACs　in　vitro.　Moreover,　the　intravascular　administration　of　the　most　potent　PAC,　PAC1a,　significantly　reduced　bacterial　burden　and　ameliorated　inflammation　level　in　a　bacteria-induced　septic　mouse　model.　This　study　presents　a　new　strategy　to　improve　the　antimicrobial　efficacy　and　biosafety　of　QACs,　thus　expanding　their　range　of　applications　to　the　treatment　of　systemic　infections.　©　2023　Elsevier　B.V.