Work

Perturbation of the Electron Transport Chain by Guanidinium‐Based Cationic Polymers Induces Metabolic Collapse in Persister‐Enriched Bacterial Populations

Year: 2026

Type: article

Abstract: ABSTRACT Bacterial persisters are widely regarded as dormant or hypometabolic cells that survive antibiotic treatment with suppressed metabolic activity. Here, we show that this apparent quiescence is accompanied by a heightened vulnerability to electron transport chain (ETC)‐associated perturbation by guanidinium‐based cationic polymers. PO 3 G, a representative polymer, preferentially kills persister‐enriched populations while markedly perturbing respiratory electron transfer. Following this ETC‐associated perturbation, persister‐enriched populations exhibit sustained superoxide‐associated oxidative stress and fail to restore NADH/NAD + homeostasis, leading to progressive loss of viability. Consistent with this ETC dependency, PO 3 G also markedly reduces persister‐enriched population induced by diverse triggers across bacterial species and achieves up to 7‐log reductions in bacterial burden in vivo. These results establish a mechanistic link between cationic polymer‐induced ETC‐associated perturbation and persister elimination, highlighting limited recovery from respiratory and redox perturbation as a vulnerability underlying the preferential killing of persisters.

Source: Angewandte Chemie International Edition

DOI: 10.1002/anie.2976200