The sentinel role of peptidoglycan recycling in the β-lactam resistance of the Gram-negative Enterobacteriaceae and Pseudomonas aeruginosa

Abstract

The peptidoglycan is the structural polymer of the bacterial cell envelope. In contrast to an expectation of a structural stasis for this polymer, during the growth of the Gram-negative bacterium this polymer is in a constant state of remodeling and extension. Our current understanding of this peptidoglycan “turnover” intertwines with the deeply related phenomena of the liberation of small peptidoglycan segments (muropeptides) during turnover, the presence of dedicated recycling pathways for reuse of these muropeptides, β-lactam inactivation of specific penicillin-binding proteins as a mechanism for the perturbation of the muropeptide pool, and this perturbation as a controlling mechanism for signal transduction leading to the expression of β-lactamase(s) as a key resistance mechanism against the β-lactam antibiotics. The nexus for many of these events is the control of the AmpR transcription factor by the composition of the muropeptide pool generated during peptidoglycan recycling. In this review we connect the seminal observations of the past decades to new observations that resolve some, but certainly not all, of the key structures and mechanisms that connect to AmpR.

Unexpected Challenges in Treating Multidrug-Resistant Gram-Negative Bacteria: Resistance to Ceftazidime-Avibactam in Archived Isolates of Pseudomonas aeruginosa

“…As stated earlier, the AmpC enzyme is responsible for the expression of ␤-lactam resistance through a complex regulatory network (16,39,41,42). Hyperexpression of this chromosomal class C ␤-lactamase involves the cell wall synthetic pathway and turnover, the AmpG permease, the AmpD amidase, and the AmpR transcriptional regulator (16,17,41,42) (Fig.…”

“…PDC expression is closely tied to cell wall recycling and can be induced after exposure to certain ␤-lactam antibiotics or hyperexpressed after various gene mutations or deletions (Fig. 1C) (15)(16)(17)(18)(19)(20). Intrinsically, the membrane of P. aeruginosa has a 12-to 100-fold-lower permeability than Escherichia coli, making it difficult for antibiotics to pass through the bacterial outer membrane (18).…”

Role of Pseudomonas aeruginosa Low-Molecular-Mass Penicillin-Binding Proteins in AmpC Expression, β-Lactam Resistance, and Peptidoglycan Structure

“…This reaction results in the repression of ampC expression, because it cleaves the inducer anhydromuropeptides and generates the peptidoglycan recycling components needed for the synthesis of the repressor UDP-MurNAc-pentapeptides. However, during exposure to AmpC-inducing ␤-lactams, MurNAc-1,6-anhydromuropeptides accumulate in the cytoplasm, leading to AmpC induction (13,14).…”

Minimal Peptidoglycan (PG) Turnover in Wild-Type and PG Hydrolase and Cell Division Mutants of Streptococcus pneumoniae D39 Growing Planktonically and in Host-Relevant Biofilms

“…In E. coli, the PG recycling pathway was recently implicated in a futile cycle that increases the efficacy of ␤-lactam antibiotics, which inhibit the transpeptidase activity of penicillin binding proteins (PBPs) (15). In some Gram-negative bacteria, such as Citrobacter freundii and Enterobacter cloacae, recycled anhydro-murotripeptide acts as an inducer for the expression of ␤-lactamase gene expression, thereby providing antibiotic resis-tance (12,16). An analogous signaling system functions in certain Gram-positive bacteria, such as Bacillus licheniformis, where recycled PG peptides (e.g., ␥-D-Glu-m-DAP [DAP is diaminopimelic acid]) relieve the expression of a ␤-lactamase gene (12).…”