A lignan compound regulates LPS modifications via PmrA/B signaling cascades to potentiate colistin efficacy in vivo

There has been a substantial gap between drying Antibiotic pipeline and ongoing Antibiotic resistance crisis, necessitating approaches to revitalize existing antimicrobials to meet unmet clinical demand for viable treatments. Herein, a lignan compound, magnolol, was identified that profoundly potentiates colistin (CS) to eradicate Gram negative bacteria and curb the development of resistance under host-mimicking condition. The mechanistic study showed that magnolol is able to disrupt PmrA/B two component signaling by dissociating the PmrA regulator protein from its cognate DNA including eptA and arnT. This action blocks the PmrA/B-dependent protective modifications of lipopolysaccharide (LPS) to reduce the net charges of Bacterial membrane, thereaby facilitating its electrostatic interaction with CS. MAG-facilitated enhancement of CS binding promotes the formation of toroidal pores in the Bacterial membrane, which in turn triggers rapid Bacterial death by inducing lethal cytoplasmic contents leakage. In sum, this work not only illustrates the great potential of untapped phytoconstitutes such as magnolol in confronting Antibiotic resistance but also reveals that silencing PmrA/B signaling as a favorable strategy to potentiate CS activity in vivo.