Bacterial cell‐wall recycling

Many Gram‐negative and Gram‐positive bacteria recycle a significant proportion of the peptidoglycan components of their cell walls during their growth and septation. In many—and quite possibly all—bacteria, the peptidoglycan fragments are recovered and recycled. Although cell‐wall recycling is beneficial for the recovery of resources, it also serves as a mechanism to detect cell‐wall–targeting antibiotics and to regulate resistance mechanisms. In several Gram‐negative pathogens, anhydro‐MurNAc‐peptide cell‐wall fragments regulate AmpC β‐lactamase induction. In some Gram‐positive organisms, short peptides derived from the cell wall regulate the induction of both β‐lactamase and β‐lactam–resistant penicillin‐binding proteins. The involvement of peptidoglycan recycling with resistance regulation suggests that inhibitors of the enzymes involved in the recycling might synergize with cell‐wall–targeted antibiotics. Indeed, such inhibitors improve the potency of β‐lactams in vitro against inducible AmpC β‐lactamase–producing bacteria. We describe the key steps of cell‐wall remodeling and recycling, the regulation of resistance mechanisms by cell‐wall recycling, and recent advances toward the discovery of cell‐wall–recycling inhibitors.