Abstact

Bacteria have evolved diverse strategies to resist antimicrobial peptides, among them lipid II-targeting lantibiotics such as nisin. PsdAB, an ABC-type transporter regulated by the PsdRS two-component system, contributes to nisin resistance, though its structural and mechanistic basis have remained unclear. Here, we report the cryo-EM structure of Bacillus subtilis PsdAB, revealing a dimeric assembly with an unusually large central cavity at the TMD interface. Cross-linking studies confirm the dimeric nature of PsdAB both in vitro and in cells. Functional assays demonstrate that dimer-disrupting mutations compromise nisin resistance, highlighting the importance of dimerization for activity. Compared to canonical ABC transporter types, PsdAB adopts an atypical architecture comprising four NBDs and two TMDs arranged around a central cavity, which may accommodate lipid II. We propose that PsdAB represents a previously unrecognized ABC transporter class. These findings offer new insights into transporter-mediated lantibiotic resistance and suggest a potential mechanism of lipid II shielding.