AmpD

AmpD is a cytosolic enzyme in many Gram-negative bacteria, functioning as a N-acetyl-anhydromuramyl-L-alanine amidase encoded by the ampD gene. It participates in peptidoglycan turnover and helps regulate the chromosomal ampC beta-lactamase. By shaping the pool of cell wall-derived signaling molecules, AmpD influences when ampC is expressed.

In Gram-negative bacteria, muropeptides generated during cell wall recycling are transported from the periplasm into the cytoplasm by the AmpG permease. AmpD hydrolyzes specific muropeptide products, limiting the concentration of 1,6-anhydro-N-acetylmuramyl-L-alanine–type signals that activate the AmpR transcriptional regulator. This action keeps ampC expression at basal levels under normal conditions.

When AmpD is inactivated or its activity is reduced, muropeptides accumulate in the cytoplasm. The increased signal activates AmpR as a transcriptional activator, leading to upregulation of ampC and high-level production of AmpC beta-lactamase. This derepression can confer resistance to a wide range of beta-lactam antibiotics and is a common mechanism behind inducible or constitutive ampC-mediated resistance in species such as Pseudomonas aeruginosa and various Enterobacterales.

Genetically, AmpD and its homologs vary by species, and some organisms harbor multiple ampD-like enzymes with differing activities. AmpD is closely linked to the AmpR-AmpC regulatory network and the muropeptide transport system, forming a key axis in beta-lactam resistance.

See also: AmpC beta-lactamase, AmpR, AmpG.