Dihalogenated indoles with antimicrobial activity against C. acnes and polymicrobial biofilms

Acne vulgaris is a chronic inflammatory skin disorder in which Cutibacterium acnes contributes to disease persistence through biofilm formation, lipid metabolism, and production of inflammatory metabolites within the pilosebaceous unit. Targeting bacterial physiological pathways that sustain these processes represents a potential therapeutic strategy beyond conventional antibiotic approaches. In this study, we evaluated a panel of halogenated indole derivatives and identified 6-bromo-4-iodoindole as a potent inhibitor of C. acnes growth and biofilm formation. The compound exhibited a minimum inhibitory concentration of 20 μg/mL and disrupted biofilm architecture. Further analyses revealed that treatment markedly altered several virulence-associated phenotypes, including reductions in extracellular lipase activity, cell-surface hydrophobicity, extracellular polymeric substance production, and porphyrin levels, accompanied by increased intracellular reactive oxygen species. Because lipase activity plays a central role in sebum metabolism and follicular colonization by C. acnes, molecular docking was performed to evaluate potential target engagement. Docking simulations suggested that 6-bromo-4-iodoindole occupies the catalytic pocket of C. acnes triacylglycerol lipase, providing a structural basis for the observed suppression of lipase-dependent phenotypes. Importantly, the compound retained biofilm inhibitory activity in polymicrobial C. acnes + Staphylococcus aureus biofilms, exhibited broad-spectrum growth inhibition extending to S. epidermidis, and significantly reduced bacterial recovery in an ex vivo porcine skin model. In silico pharmacokinetic analyses further indicated physicochemical properties compatible with localized topical delivery. Together, these findings demonstrate that a dihalogenated indole reduces lipase-associated virulence related phenotypes in C. acnes and suppresses biofilm formation in skin-relevant environments, supporting further investigation of this scaffold as a therapeutic strategy targeting acne-associated microbial physiology.