Pixantrone sensitizes superbugs to rifampin by ROS induction and proton dynamic potential disruption

The emergence of bacterial drug resistance poses a severe threat to global public health. In particular, antimicrobial-resistant pathogens lead to a high rate of treatment failure and significantly increase mortality. Repurposing FDA-approved compounds to sensitize superbugs to conventional antibiotics provides a promising strategy to alleviate such crises. Pixantrone (PIX) has been approved for treating aggressive B-cell non-Hodgkin's lymphoma. By high-throughput drug screening, we profiled the synergistic activity between PIX and rifampin (RFP) against gram-negative extensively drug-resistant isolates by checkerboard assay. Mechanistic studies demonstrated that PIX induced irreversible intracellular ROS accumulation, disrupted proton motive force and interrupted topoisomerase. In addition, the combination of PIX with RFP possesses effective antimicrobial activity against multidrug-resistant strains in vivo without detected toxicity. Collectively, these results reveal the potential of PIX in combination with RFP as a therapy option for refractory infections caused by gram-negative pathogens.