Table 1.
Key TCSs that are reportedly or potentially associated with virulence and/or antibiotics resistance in P. aeruginosa, A. baumannii and K. pneumoniae.
| Name of the Two-Component System | Confirmed or Predicted Function | Reference(s) |
|---|---|---|
| P. aeruginosa | ||
| PhoQ/PhoP | Regulating ABC transporter system; Resistance to antimicrobial peptides, polymyxins, and aminoglycosides; Regulating virulence, swarming motility and biofilm formation; Mg2+ sensing. | [130,131,132,133] |
| PmrA/PmrB | Activated by low Mg2+ and cationic antimicrobial peptides; Resistance against polymyxin B, colistin and other antimicrobial peptides | [131,134,135] |
| CpxA/CpxR | Role in cell envelope stress response; Activates MexAB-OprM efflux pump expression | [136] |
| CprS/CprR | Role in LPS modification and antimicrobial peptide resistance | [137] |
| ParR/ParS | Role in resistance to colistin and polymyxins; Role in quorum sensing, phenazine production, and motility | [137,138] |
| GacS/GacA | Regulating virulence factors; Biofilm formation; Antibiotic resistance; Motility; Iron metabolism; Type III and type VI secretion | [139] |
| PvrS/PvrR | Regulation of the MexAB-OprM efflux pump; Biofilm formation. Controls of fimbrial genes | [140,141,142,143] |
| RcsC-RcsB | Role in biofilm formation and control of fimbrial genes | [140,141] |
| AmgS-AmgR | Involved in aminoglycoside resistance and cell envelope stress response | [144,145,146] |
| PA1611 | Biofilm formation and virulence regulation | [96,129] |
| BfiS/BfiR | Biofilm maturation | [147] |
| HptB/HsbR | Involved in swarming motility and biofilm formation | [148,149] |
| RocS2/RocA2 | Regulation of fimbrial adhesins and antimicrobial resistance | [143,150] |
| ErbR/EraR | Control of biofilm specific antibiotic resistance | [151] |
| TctE/TctD | Controls expression of tricarboxylic acid (TCA) uptake system | [86] |
| PhoR–PhoB | Plays a role in quorum sensing and swarming motility | [86,152] |
| ChpA/PilG/PilH/ChpB | Regulation of the chemosensory pili (Pil–Chp) system, twitching motility and cAMP levels; Regulates virulence genes | [153,154] |
| FimS (AlgZ)/AlgR | Regulation of virulence; Alginate biosynthesis; Motility; Biofilm formation; Cytotoxicity and type III secretion system expression | [155] |
| ColS/ColR | Polymyxin resistance; Virulence and cell adherence | [20] |
| CreC–CreB | Role in catabolism; Swarming and swimming motility; Antibiotic resistance; Biofilm and global gene regulation | [156] |
| PirR–PirS | Iron acquisition | [157] |
| FleS–FleR | Flagellar motility; Adhesion to mucins | [158] |
| PA1396/PA1397 | Plays a role in interspecies signaling; Responds to diffusible signal factor (DSF); Regulates biofilm formation and antibiotic resistance | [159] |
| CzcS–CzcR | Regulates heavy metal resistance; Controls antibiotic resistance and pathogenicity | [160,161] |
| RetS | Regulates virulence; Biofilm formation; Regulates Type III and VI secretion/cytotoxicity | [99,162] |
| LadS | Regulates virulence; Biofilm formation; Type III secretion/cytotoxicity | [99,101] |
| BqsS/BqrR/CarS/CarR | Biofilm formation; Iron sensing; Antibiotic resistance and cationic stress tolerance. Maintains Ca2+ homeostasis; Regulates pyocyanin secretion; Motility. | [163] |
| PfeS–PfeR | Iron acquisition | [87] |
| CopS–CopR | Tolerance to Cu2+, Zn2+; Imipenem resistance | [161] |
| GtrS/GltR | Regulates glucose transport and Type III secretion system | [164,165] |
| WspE–WspR | Regulates biofilm formation, autoaggregation, and cyclic-di-GMP synthesis | [166,167,168] |
| NarX–NarL | Nitrate sensing and respiration; Biofilm formation; Motility | [84] |
| BfmS/BfmR | Biofilm formation/maintenance | [147] |
| PprA–PprB | Regulates outer membrane permeability; Aminoglycoside resistance; Controls virulence including type III secretion system and biofilm formation | [169,170,171] |
| RoxS/RoxR | Confers cyanide tolerance | [172] |
| PilS–PilR | Involved in regulating the expression of the T4P major subunit PilA; Biofilm formation; Motility; Positively regulates the transcription of flagellar regulatory genes | [173] |
| CbrA–CbrB | Metabolic regulation of carbon and nitrogen utilization. Modulates biofilm formation; Cytotoxicity; Motility; Antibiotic resistance | [89] |
| AruS/AruR | Controls the expression of the arginine transaminase pathway | [174,175] |
| NtrB/NtrC | Responds to cellular nitrogen levels and activates nitrogen scavenging genes | [176] |
| DctB/DctD | Controls the expression of C4-dicarboxylate transporters | [177] |
| KinA/AlgB | Regulates alginate biosynthesis; Regulates virulence | [178] |
| MifS/MifR | Role in biofilm formation and metabolism | [179] |
| K. pneumoniae | ||
| CpxA/CpxR | Sensing extracellular pH and membrane composition; Regulating cell envelope protein folding and protein degradation | [180,181] |
| PhoP/PhoQ | Activates pmrHFIJKLM; Responsible for L-amino arabinose synthesis and polymyxin resistance | [182,183,184] |
| PhoR/PhoB | Phosphate assimilation | [180] |
| QseC/QseB | Involved in regulation of the flagella and motility genes | [185] |
| KvgA/KvgS | Involved in tolerating free radical stresses and sensing iron-limiting conditions | [186] |
| KvhA/KvhS | Regulates capsular polysaccharide synthesis | [187,188] |
| PmrA/PmrB | Regulator of genes for lipopolysaccharide modification | [189] |
| RcsC/RcsB | Involved in the capsular polysaccharide biosynthesis; Type III system; Regulates the production of major pilin protein MrkA; Confers resistance to low pH | [190] |
| EnvZ/OmpR | Senses osmotic signals; Regulates the c-di-GMP signaling pathway; Regulates type III fimbriae and biofilm formation | [191,192,193] |
| CusS/CusR | Induced by Copper and regulates the CusCFBARS efflux system; Tolerance to silver | [194,195,196] |
| KdpD/KdpE | Potassium transporter system | [197,198,199] |
| BaeS/BaeR | Regulates Multidrug efflux pump AdeABC; Regulates Modification of lipopolysaccharides | [199,200] |
| ArcB/ArcA | Involved in modulating the expression of genes encoding for proteins with membrane modification functions and TCA cycle enzymes depending upon oxygen levels. | [199,201] |
| NarX/NarL | Role in nitrate and nitrite reductase synthesis | [202,203] |
| UhpB/UhpA | Role in uptake of hexose phosphates | [199,204,205] |
| EvgS/EvgA | Regulates capsular polysaccharide biosynthesis | [206,207] |
| GlnL/GlnG | Role in glutamate metabolism | [208,209] |
| ZraR/ZraS | Zinc-responsive TCS; Activated under high calcium and iron conditions | [210] |
| CitA/CitB | Regulates citrate metabolism under anaerobic conditions | [211,212] |
| CrrA/CrrB | Involved in polymyxin resistance | [213] |
| A. baumannii | ||
| PmrA/PmrB | Regulates genes involved in lipopolysaccharide modification | [214,215] |
| AdeS/AdeR | Regulates genes encoding the AdeABC pump | [59,216] |
| BaeS/BaeR | Stress response under high osmotic conditions | [60,217,218] |
| BfmS/BfmR | Regulates biofilm formation and antibiotic resistance | [219,220,221] |
| GacS/GacA | Regulates genes associated with pili and biofilm development, motility and resistance against host antimicrobial peptides | [222,223] |
| A1S_2811 | Involved in surface motility and biofilm formation | [224] |
| KdpD/KpdE | Regulates potassium transport | [225] |
| GlnL/GlnG | Involved in nitrogen assimilation | [226] |
| PhoR/PhoB | Regulates phosphate assimilation | [227] |
| CusS/CusR | Senses copper ions and upregulates the expression of an RND family efflux pump that removes copper ions from the cell | [228] |
| OmpR/EnvZ | Regulates virulence; Phase variation; Osmotic tolerance | [229] |