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

• Published in: Bioorganic chemistry Vol. 56; pp. 41 - 48
• Main Authors: Fisher, Jed F., Mobashery, Shahriar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2014
• Subjects: AmpC; AmpD; AmpG; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Bactoprenol; beta-Lactam Resistance - drug effects; beta-Lactamases - metabolism; beta-Lactams - chemistry; beta-Lactams - pharmacology; Enterobacteriaceae - drug effects; Enterobacteriaceae - enzymology; Enterobacteriaceae - metabolism; Microbial Sensitivity Tests; Muropeptide; NagZ; PBP; Peptidoglycan - chemistry; Peptidoglycan - metabolism; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - enzymology; Pseudomonas aeruginosa - metabolism; Undecaprenol; AmpC; LMM PBP; NagZ; HMM PBP; LTTR; Bactoprenol; Muropeptide; Undecaprenol; LT; AmpG; AmpD; PBP
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2014.05.011

[Display omitted] •Gram-negative bacterial infections often are treated with β-lactam antibiotics.•β-Lactam antibiotics target the peptidoglycan polymer of the bacterium.•The peptidoglycan of Gram-negative bacteria is continuously remodeled.•Bacteria sense the presence of β-lactams by their effect on peptidoglycan remodeling.•Blocking this signaling pathway may subvert bacterial antibiotic resistance. 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.