Structural, functional, and mechanistic studies of the bacterial divisome FtsWIQBL in complex with antibiotics.

Septal peptidoglycan (sPG) biosynthesis during bacterial cell division is driven by the dynamic divisome complex. Its core components, glycosyltransferase FtsW and transpeptidase FtsI are responsible for glycan chain polymerization and crosslinking, respectively. FtsI is also the target of β-lactams. The essential membrane complex FtsQ-FtsB-FtsL regulates FtsWI enzymatic activity. However, the mechanism of FtsQBLWI-mediated sPG synthesis and β-lactam-induced conformational changes have remained elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of the Pseudomonas aeruginosa FtsQBLWI complex in the apo state and bound to aztreonam or imipenem. Our work reveals intricate structural details, including the putative substrate-binding cavities of FtsW, FtsI-mediated allosteric activation of FtsW, and β-lactam-triggered conformational rearrangements. Collectively, these structural, genetic and biochemical analyses reveal the mechanism of FtsQBLWI-controlled sPG synthesis and β-lactam action on this complex, providing a molecular basis for optimizing existing β-lactams and developing novel antibiotics.