Table 1.

Main phenomena suggesting the existence of PGN-derived signaling impacting the fitness/virulence of Gram-negatives.

Sensor/regulator	Species	Phenomenon	Effector PGN fragment	References
AmpR (LysR-type regulator)	K. pneumoniae	The presence of AmpR regulators codified together with horizontally acquired class C β-lactamases is associated with increased capsule synthesis and virulence	Unknown	Hennequin et al. (2012), Zhang et al. (2020)
AmpR (LysR-type regulator)	P. aeruginosa	Activator role for acute virulence factors and repressor for biofilm formation	Unknown	Balasubramanian et al. (2011, 2012, 2015)
AmpR (LysR-type regulator)	S. maltophilia	Repressor for the production of the principal quorum sensing signal (DSF), impairing biofilm formation, oxidative stress resistance, and general virulence	Unknown	Alcaraz et al.(2022)
CreBC (two-component system)	P. aeruginosa	Major role contributing to bacterial fitness and biofilm development, especially through its effector inner membrane protein CreD, proportionally expressed with regards to CreBC operon	Unknown	Zamorano et al. (2014)
CreBC (two-component system)	S. maltophilia	Maintenance of cell envelope integrity, promotor of protease secretion, and repressor of motility. Repressor for CreD expression	Unknown	Huang et al. (2015a, b)
CpxAR-CpxP	Multiple species	Multiple studies demonstrating that CpxA is able to sense muropeptide alterations in the periplasm, and others that CpxR is a bona fide regulator of virulence-related genes. Depending on the study/species, the effect of CpxR seems to be a promotor vs. repressor of bacterial pathogenesis. Proposed mechanism: under certain conditions (e.g. β-lactam challenge), the soluble muropeptide pool in the periplasm allegedly changes, and then the differentially accumulated fragments could competitively displace CpxP from CpxA EBD (to which it is bound in regular conditions so as to keep the system switched off). This circumstance would enable CpxA autokinase activity and the subsequent phosphorylation of CpxR, finally promoting/repressing the expression of genes under its control	Unknown	Humphreys et al. (2004), Fleischer et al. (2007), MacRitchie et al. (2008), Mitobe et al. (2011), Liu et al. (2012), Debnath et al. (2013), Weatherspoon-Griffin et al. (2011), Tschauner et al. (2014), Bontemps-Gallo et al. (2015), Acosta et al. (2015), De la Cruz et al. (2015, 2016), Tanner et al. (2016), Gangaiah et al. (2017), Li et al. (2018), Xie et al. (2018), Subramaniam et al. (2019), Thanikkal et al. (2019), Vogt et al. (2019), Masi et al. (2020), Wu et al. (2021)
AgtR (?)	P. aeruginosa	Increased transcription of the pqs operon, responsible for the quorum sensing signal PQS, which in turn promotes the production of pyocyanin and proteases	GlcNAc alone or larger GlcNAc-containing PGN fragments, providing phosphorylated GlcNAc derivatives through NagE phosphotranferase	Korgaonkar and Whiteley (2011), Korgaonkar et al. (2013), Lee and Zhang (2015)
LuxR-type receptors (binding site for quorum sensing signals)	P. aeruginosa, C. violaceum, and E. coli	Partial inhibition of the transcription of genes controlled by quorum sensing-linked LuxR-type regulators, including important virulence-related actors such as elastases and proteases	Phosphorylated GlcNAc derivatives provided by NagE	Lee and Zhang (2015), Kimyon et al. (2016)
Unknown	E. coli	Downregulation of two extracellular adhesion factors: type 1 fimbrial adhesins and extracellular curli fibers. Decrease of the elicited inflammatory response, thus promoting dissemination	GlcNAc-6-phosphate	Sohanpal et al. (2004, 2007), Barnhart et al. (2006), Naseem and Konopka (2015)
Unknown	E. coli	Prevention of quiescence status that appears at low population density. Therefore, promotion of quorum sensing-independent growth	Tetra- or penta-peptide stem chains, both from Gram-positive or -negative bacteria	DiBiasio et al. (2020)
Unknown	E. coli, P. aeruginosa	Rescue cells from stationary phase, resuming growth even in a scenario of nutrient scarcity	1,6-anhydro-MurNAc-GlcNAc-peptides	Jõers et al. (2019)
Unknown	Salmonella enterica, R. solanacearum	Accumulation of muropeptides due to cytosolic AmpD amidase disruption leads to reduced fitness and virulence attenuation	Unknown	Tans-Kersten et al. (2000), Folkesson et al. (2005)
Unknown	X. campestris	Accumulation of muropeptides due to cytosolic NagZ glucosaminidase disruption leads to virulence attenuation	Unknown	Yang et al. (2014)

‘?’ indicates that this is the most plausible element involved in the PGN sensing/response, although not fully demonstrated. Abbreviations; DSF: diffusible signal factor; EBD: effector-binding domain; GlcNAc: N-acetyl glucosamine; PGN: peptidoglycan; and PQS: 2-heptyl-3-hydroxy-4-quinolone.