TABLE 7.

Elements simultaneously involved in regulation of expression of intrinsic β-lactamases and PGN metabolism

Target	Role(s)	Species	Effect(s) of target disruption	Reference(s)
AmpR	A LysR-type global transcriptional regulator controlling the expression of ampC and other genes related to virulence, quorum sensing, biofilm formation, etc.	P. aeruginosa	A significant reduction of the ability to kill Caenorhabditis elegans with AmpR inactivation; with the G154R AmpR mutation, prevalent in the ST175 high-risk clone, reduced virulence in the same model of infection	267
CreBC/CreD	For CreBC, a two-component system and global metabolic regulator involved in the response against stress or biofilm growth, among others; for CreD an inner membrane effector protein of the CreBC system	P. aeruginosa	A decrease in fitness in in vitro competition experiments compared with that of the wild type, mainly in the presence of β-lactams; a decrease in the formation of biofilms, mainly in the presence of β-lactams; decrease of exoS expression, especially in the presence of ceftazidime	276
AmpD-AmpDh2-AmpDh3	N-Acetyl-anhydromuramyl-l-alanine amidases that are involved in PGN turnover and recycling as well as AmpC repression and that are cytoplasmic (AmpD) or periplasmic and involved in stem peptide cleavage (AmpDh2 and AmpDh3)	P. aeruginosa	Severely compromised growth rates, motility, and cytotoxicity in the triple mutant; repression in key virulence factors, such as protease LasA, phospholipase C, or T3SS components; decreased virulence of circa 100-fold in Galleria mellonella model	223
NagZ, AmpG, and AmpD-AmpDh2-AmpDh3	Key elements allowing PGN recycling (see the text for further details)	P. aeruginosa	Increased susceptibility to lysozyme and human PGRPs; if PGN blockade is combined with AmpC hyperproduction (for the AmpD-AmpDh2-AmpDh3 triple mutant), an even higher increase in susceptibility to lysozyme and PGRP2 specifically	203
CreBC	A two-component system and global metabolic regulator involved in the response against stress	S. maltophilia	A decrease in secreted protease activity	277
AmpD	A cytosolic 1,6-anhydro-N-acetylmuramyl– l-alanine amidase cleaving the stem peptide from 1,6-anhydro-N-acetylmuramic acid in a key step for PGN recycling	Salmonella enterica serovar Typhimurium	Upregulation during infection; in a knockout mutant, a decreased capacity to invade macrophages and more potent induction of the nitric oxide response of bacterial killing; decreased competitiveness in a BALB/c mouse model of infection	85, 99
AmpD	A cytosolic 1,6-anhydro-N-acetylmuramyl–l-alanine amidase involved in PGN recycling	N. meningitidis	An inability to cause systemic infection in an infant rat model; in wild-type strains, hyperexpression of AmpD during infection	84
AmpD	A cytosolic 1,6-anhydro-N-acetylmuramyl–l-alanine amidase cleaving the stem peptide from 1,6-anhydro-N-acetylmuramic acid in a key step for PGN recycling	Ralstonia solanacearum	Upregulation during infection; in a knockout mutant, reduced virulence in eggplant and tomato models	85, 98
NagZxc	A β-N-acetylglucosaminidase that cleaves the bond between 1,6-anhydro-N-acetylmuramic acid and N-acetylglucosamine	X. campestris	Reduced average lesion areas in cabbage infection model	232
AmpGxc	A specific permease for PGN fragments containing the disaccharide N-acetylmuramic acid–N-acetylglucosamine	X. campestris	Slightly increased average lesion areas in cabbage infection model	232
AmpC	A class C β-lactamase (noninducible due to the lack of the AmpR regulator in E. coli)	E. coli	In AmpH-AmpC double mutants, uneven contours and aberrant and asymmetric constrictions between dividing cells	255