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.

Keywords: AmpC; AmpD; AmpG; Bactoprenol; Muropeptide; NagZ; PBP; Undecaprenol.

Scheme 1

Principal events in the synthesis, turnover, and recycling of the peptidoglycan of the Gram-negative bacterium, segregated with respect to the events of the cytoplasm (lower), inner membrane (center), and the periplasmic space between the inner membrane and outer membrane (upper). Peptidoglycan turnover and recycling comprises events that proceed clockwise from the periplasm (upper center), through the inner membrane (center right) and into the cytoplasm (lower right). The key steps (labeled as Step 1 through Step 6) are further illustrated in Scheme 2. This figure is adapted from Johnson et al. [23] and is used with permission.

Scheme 2

The key events known to occur in peptidoglycan recycling that directly affect control of the expression of resistance pathways through the AmpR transcription factor network, especially expression of the AmpC β-lactamase. The steps (also shown in Scheme 1) illustrate the probable events leading to the muropeptide structure 6c as a repressor of AmpC expression acting through AmpR (normal peptidoglycan recycling), and muropeptide 8c as a depressor of AmpC expression acting through AmpR (perturbed peptidoglycan recycling leading to induction of resistance pathways).