β-Lactamase Induction in Gram-Negative Bacteria Is Intimately Linked to Peptidoglycan Recycling

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Abstract
A number of Gram-negative organisms normally express a chromosomall y mediated class C β-lactamase that is inducible by β-lactam antibiotics. Data have recently emerged suggesting a close link between β-lactamase induction and the recycling of released muramyl peptides from the bacterial peptidoglycan. Thus the AmpG transporter is responsible for the uptake into the cell of GlcNAc–anhMurNAc-tripeptide. A mutant unable to express AmpG is therefore unable to recycle the cell wall and is at the same time not possible to induce by a β-lactam. Once inside the cytosol the above muramyl peptide and its derivative anhMurNAc-tripeptide is degraded by the cytosolic AmpD amidase that specifically releases the tripeptide from cytosolic muramyl peptides brought into the cell via AmpG. Mutants unable to produce AmpD are blocked in a cytosolic step for cell wall recycling and accumulate large amounts of cytosolic anhMurNAc-tripeptide. It is believed that cytosolic muramyl peptides can act as ligands for the β-lactamase regulator AmpR to activate expression of β-lactamase. AmpD mutants, therefore, constitutively overproduce the chromosomal β-lactamase and are β-lactam resistant. In wild-type strains β-lactams that result in an increased cell wall breakdown will cause an increase in the cytosol of muramyl peptides leading to β-lactamase induction. Mutants affected in the ampD gene arise readily during treatment with third-generation cephalosporins. Since these mutants lack a functional cell wall recycling system they may be at a disadvantage in the absence of selection. However, since muramyl peptides may act as cytotoxins, especially for respiratory epithelial cells, ampD mutants due to their large accumulation of anhMurNAc-tripeptide may be altered in their pathogenic properties as compared to wild-type cells possessing a normal cell wall recycling system.