Staphylococcus aureus can cause a wide variety of diseases, which are attributed to its large repertoire of virulence factors, many of which are under the control of two component sensing systems (TCS). These systems allow the pathogen to alter and regulate its gene expression profile under the environmental stimuli. A simple TCS system is composed of a membrane associated histidine kinase and response regulator which is mainly present in cytosol. There is a total of sixteen such systems in Staphylococcus aureus which are involved in diverse signaling cascades including response to antimicrobial agents, nutrient sensing, chemotaxis, virulent gene regulation and biofilm formations. Most of these systems are interlinked and influence each other to regulate virulence profile of the pathogen. In this study, we summarize our current understanding of these systems and their different component in methicillin resistant Staphylococcus aureus which will have important implications in structure-based approaches for designing novel class of small molecule inhibitors to combat Staphylococcal infections.

1.
Sivaraman
GK
,
Muneeb
KH
,
Sudha
S
,
Shome
B
,
Cole
J
,
Holmes
M.
Prevalence of virulent and biofilm forming ST88-IV-t2526 methicillin-resistant Staphylococcus aureus clones circulating in local retail fish markets in Assam, India
.
Food Control.
2021
Sep;
127
:
108098
.
2.
Enright
MC
,
Robinson
DA
,
Randle
G
,
Feil
EJ
,
Grundmann
H
,
Spratt
BG
.
The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA
).
Proceedings of the National Academy of Sciences.
2002
May 28;
99
(
11
):
7687
92
.
3.
Harkins
CP
,
Pichon
B
,
Doumith
M
,
Parkhill
J
,
Westh
H
,
Tomasz
A
, et al
Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice
.
Genome Biology.
2017
Dec 20;
18
(
1
):
130
.
4.
Gould
IM
,
David
MZ
,
Esposito
S
,
Garau
J
,
Lina
G
,
Mazzei
T
, et al
New insights into meticillinresistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance
.
International Journal of Antimicrobial Agents.
2012
Feb;
39
(
2
):
96
104
.
5.
Moreillion
P
,
Que
YA
,
Glauser
M.
Staphylococcus aureus (Including Staphyloccal Toxic shock). In
‘Principles and Practice of Infectious diseases
.’
Published by Churchill Livingstone Pennyslyvania
.
2005
Jan 1
;
2
:
2333
9
.
6.
Foster
TJ
,
Geoghegan
JA
. Staphylococcus aureus. In:
Molecular Medical Microbiology
.
Elsevier
;
2015
. p.
655
74
.
7.
Zheng
X
,
Marsman
G
,
Lacey
KA
,
Chapman
JR
,
Goosmann
C
,
Ueberheide
BM
, et al
The cell envelope of Staphylococcus aureus selectively controls the sorting of virulence factors
.
Nature Communications.
2021
Dec 26;
12
(
1
):
6193
.
8.
Barrientos
L
,
Mercier
N
,
Lalaouna
D
,
Caldelari
I.
Assembling the Current Pieces: The Puzzle of RNA-Mediated Regulation in Staphylococcus aureus
.
Frontiers in Microbiology.
2021
Jul 21;
12
.
9.
West
AH
,
Stock
AM
.
Histidine kinases and response regulator proteins in two-component signaling systems
.
Trends in Biochemical Sciences.
2001
Jun;
26
(
6
):
369
76
.
10.
Jenul
C
,
Horswill
AR
.
Regulation of Staphylococcus aureus Virulence
.
Microbiology Spectrum.
2019
Apr 12;
7
(
2
).
11.
Dehbashi
S
,
Tahmasebi
H
,
Zeyni
B
,
Arabestani
MR
.
Regulation of virulence and β-lactamase gene expression in Staphylococcus aureus isolates: cooperation of two-component systems in bloodstream superbugs
.
BMC Microbiology.
2021
Dec 25;
21
(
1
):
192
.
12.
Bourret
RB
,
Silversmith
RE
.
Measuring the Activities of Two-Component Regulatory System Phosphatases
. In
2018
. p.
321
51
.
13.
Lade
H
,
Kim
J-S.
Bacterial Targets of Antibiotics in Methicillin-Resistant Staphylococcus aureus
.
Antibiotics.
2021
Apr 7;
10
(
4
):
398
.
14.
Ji
Q
,
Chen
PJ
,
Qin
G
,
Deng
X
,
Hao
Z
,
Wawrzak
Z
, et al
Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus
.
Nature Communications.
2016
Apr 22;
7
(
1
):
11000
.
15.
Jumper
J
,
Evans
R
,
Pritzel
A
,
Green
T
,
Figurnov
M
,
Ronneberger
O
, et al.
Highly accurate protein structure prediction with
AlphaFold
.
Nature.
2021
Aug 26;
596
(
7873
):
583
9
.
16.
Donaldson
LW
.
The NMR Structure of the Staphylococcus aureus Response Regulator VraR DNA Binding Domain Reveals a Dynamic Relationship between It and Its Associated Receiver Domain
.
Biochemistry.
2008
Mar 1;
47
(
11
):
3379
88
.
17.
Leonard
PG
,
Golemi-Kotra
D
,
Stock
AM
.
Phosphorylation-dependent conformational changes and domain rearrangements in Staphylococcus aureus VraR activation
.
Proceedings of the National Academy of Sciences.
2013
May 21;
110
(
21
):
8525
30
.
18.
Fan
X
,
Zhang
X
,
Zhu
Y
,
Niu
L
,
Teng
M
,
Sun
B
, et al
Structure of the DNA-binding domain of the response regulator SaeR from Staphylococcus aureus
.
Acta Crystallographica Section D Biological Crystallography.
2015
Aug 1;
71
(
8
):
1768
76
.
19.
Ouyang
Z
,
Zheng
F
,
Chew
JY
,
Pei
Y
,
Zhou
J
,
Wen
K
, et al
Deciphering the activation and recognition mechanisms of Staphylococcus aureus response regulator ArlR
.
Nucleic Acids Research.
2019
Dec 2;
47
(
21
):
11418
29
.
20.
Sharma-Kuinkel
BK
,
Mann
EE
,
Ahn
J-S
,
Kuechenmeister
LJ
,
Dunman
PM
,
Bayles
KW
.
The Staphylococcus aureus LytSR Two-Component Regulatory System Affects Biofilm Formation
.
Journal of Bacteriology.
2009
Aug;
191
(
15
):
4767
75
.
21.
Tiwari
N
,
López-Redondo
M
,
Miguel-Romero
L
,
Kulhankova
K
,
Cahill
MP
,
Tran
PM
, et al
The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines
.
Proceedings of the National Academy of Sciences.
2020
May 19;
117
(
20
):
10989
99
.
22.
Sangare
L
,
Chen
W
,
Wang
C
,
Chen
X
,
Wu
M
,
Zhang
X
, et al
Structural insights into the conformational change of Staphylococcus aureus NreA at C-terminus
.
Biotechnology Letters.
2020
May 22;
42
(
5
):
787
95
.
23.
Dutta
A
,
Batish
M
,
Parashar
V.
Structural basis of KdpD histidine kinase binding to the second messenger c-di-AMP
.
Journal of Biological Chemistry.
2021
Jan;
296
:
100771
.
24.
Xue
T
,
You
Y
,
Hong
D
,
Sun
H
,
Sun
B.
The Staphylococcus aureus KdpDE Two-Component System Couples Extracellular K + Sensing and Agr Signaling to Infection Programming
.
Infection and Immunity.
2011
Jun;
79
(
6
):
2154
67
.
25.
Zhao
L
,
Xue
T
,
Shang
F
,
Sun
H
,
Sun
B.
Staphylococcus aureus AI-2 Quorum Sensing Associates with the KdpDE Two-Component System To Regulate Capsular Polysaccharide Synthesis and Virulence
.
Infection and Immunity.
2010
Aug;
78
(
8
):
3506
15
.
26.
Moscoso
JA
,
Schramke
H
,
Zhang
Y
,
Tosi
T
,
Dehbi
A
,
Jung
K
, et al
Binding of Cyclic Di-AMP to the Staphylococcus aureus Sensor Kinase KdpD Occurs via the Universal Stress Protein Domain and Downregulates the Expression of the Kdp Potassium Transporter
.
Journal of Bacteriology.
2016
Jan;
198
(
1
):
98
110
.
27.
Falord
M
,
Mäder U
,
Hiron
A
,
Débarbouillé
M,
Msadek
T.
Investigation of the Staphylococcus aureus GraSR Regulon Reveals Novel Links to Virulence, Stress Response and Cell Wall Signal Transduction Pathways
.
PLoS ONE.
2011
Jul 1;
6
(
7
):
e21323
.
28.
Muzamal
U
,
Gomez
D
,
Kapadia
F
,
Golemi-Kotra
D.
Diversity of two-component systems: insights into the signal transduction mechanism by the Staphylococcus aureus two-component system GraSR
.
F1000Research.
2014
Nov 17;
3
:
252
.
29.
Stauff
DL
,
Skaar
EP
. The Heme Sensor System of Staphylococcus aureus
In: Bacterial Sensing and Signaling
.
Basel
:
KARGER
;
2009
. p.
120
35
.
30.
Arii
K
,
Kawada-Matsuo
M
,
Oogai
Y
,
Noguchi
K
,
Komatsuzawa
H.
Single mutations in BraRS confer high resistance against nisin A in Staphylococcus aureus
.
MicrobiologyOpen.
2019
Nov 17;
8
(
11
).
31.
Hiron
A
,
Falord
M
, Valle
J
,
Débarbouillé
M,
Msadek
T.
Bacitracin and nisin resistance in Staphylococcus aureus: a novel pathway involving the BraS/BraR two-component system (SA2417/SA2418) and both the BraD/BraE and VraD/VraE ABC transporters
.
Molecular Microbiology.
2011
Aug;
81
(
3
):
602
22
.
32.
Kelliher
JL
,
Radin
JN
,
Kehl-Fie
TE
.
PhoPR Contributes to Staphylococcus aureus Growth during Phosphate Starvation and Pathogenesis in an Environment-Specific Manner
.
Infection and Immunity.
2018
Oct;
86
(
10
).
33.
Hall
JW
,
Yang
J
,
Guo
H
,
Ji
Y.
The AirSR two-component system contributes to Staphylococcus aureus survival in human blood and transcriptionally regulates sspABC operon
.
Frontiers in Microbiology.
2015
Jul 3;
6
.
34.
Sun
H
,
Yang
Y
,
Xue
T
,
Sun
B.
Modulation of cell wall synthesis and susceptibility to vancomycin by the two-component system AirSR in Staphylococcus aureus NCTC8325
.
BMC Microbiology.
2013
;
13
(
1
):
286
.
35.
Park
JY
,
Kim
JW
,
Moon
BY
,
Lee
J
,
Fortin
YJ
,
Austin
FW
, et al
Characterization of a Novel Two-Component Regulatory System, HptRS, the Regulator for the Hexose Phosphate Transport System in Staphylococcus aureus
.
Infection and Immunity.
2015
Apr;
83
(
4
):
1620
8
.
36.
Reed
JM
,
Olson
S
,
Brees
DF
,
Griffin
CE
,
Grove
RA
,
Davis
PJ
, et al
Coordinated regulation of transcription by CcpA and the Staphylococcus aureus two-component system HptRS
.
PLOS ONE.
2018
Dec 12;
13
(
12
):
e0207161
.
37.
Yang
Y
,
Sun
H
,
Liu
X
,
Wang
M
,
Xue
T
,
Sun
B.
Regulatory mechanism of the three-component system HptRSA in glucose-6-phosphate uptake in Staphylococcus aureus
.
Medical Microbiology and Immunology.
2016
Jun 28;
205
(
3
):
241
53
.
38.
Srivastava
SK
,
Rajasree
K
,
Fasim
A
,
Arakere
G
,
Gopal
B.
Influence of the AgrC-AgrA Complex on the Response Time of Staphylococcus aureus Quorum Sensing
.
Journal of Bacteriology.
2014
Aug;
196
(
15
):
2876
88
.
39.
Rajasree
K
,
Fasim
A
,
Gopal
B.
Conformational features of the Staphylococcus aureus AgrA-promoter interactions rationalize quorum-sensing triggered gene expression
.
Biochemistry and Biophysics Reports.
2016
Jul;
6
:
124
34
.
40.
Sidote
DJ
,
Barbieri
CM
,
Wu
T
,
Stock
AM
.
Structure of the Staphylococcus aureus AgrA LytTR Domain Bound to DNA Reveals a Beta Fold with an Unusual Mode of Binding
.
Structure.
2008
May;
16
(
5
):
727
35
.
41.
Leonard
PG
,
Bezar
IF
,
Sidote
DJ
,
Stock
AM
.
Identification of a Hydrophobic Cleft in the LytTR Domain of AgrA as a Locus for Small Molecule Interactions That Inhibit DNA Binding
.
Biochemistry.
2012
Dec 18;
51
(
50
):
10035
43
.
42.
Huemer
M
,
Mairpady
Shambat
S,
Bergada-Pijuan
J
,
Söderholm
S
,
Boumasmoud
M
,
Vulin
C
, et al
Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success
.
Proceedings of the National Academy of Sciences.
2021
Feb 16;
118
(
7
):
e2014920118
.
43.
Jung
K
,
Fried
L
,
Behr
S
,
Heermann
R.
Histidine kinases and response regulators in networks
.
Current Opinion in Microbiology.
2012
Apr;
15
(
2
):
118
24
.
44.
Haag
AF
,
Bagnoli
F.
The Role of Two-Component Signal Transduction Systems in Staphylococcus aureus Virulence Regulation
. In
2015
. p.
145
98
.
45.
Buschiazzo
A
,
Trajtenberg
F.
Two-Component Sensing and Regulation: How Do Histidine Kinases Talk with Response Regulators at the Molecular Level?
Annual Review of Microbiology.
2019
Sep 8;
73
(
1
):
507
28
.
46.
Lionta
E
,
Spyrou
G
,
Vassilatis
D
,
Cournia
Z.
Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances
.
Current Topics in Medicinal Chemistry.
2014
Oct 15;
14
(
16
):
1923
38
.
47.
Kalyaanamoorthy
S
,
Chen
Y-PP
.
Structure-based drug design to augment hit discovery
.
Drug Discovery Today.
2011
Sep;
16
(
17–18
):
831
9
.
48.
Bhate
MP
,
Molnar
KS
,
Goulian
M
,
DeGrado
WF
.
Signal Transduction in Histidine Kinases: Insights from New Structures
.
Structure.
2015
Jun;
23
(
6
):
981
94
.
49.
Casino
P
,
Rubio
V
,
Marina
A.
The mechanism of signal transduction by two-component systems
.
Current Opinion in Structural Biology.
2010
Dec;
20
(
6
):
763
71
.
50.
Casino
P
,
Rubio
V
,
Marina
A.
Structural Insight into Partner Specificity and Phosphoryl Transfer in Two-Component Signal Transduction
.
Cell.
2009
Oct;
139
(
2
):
325
36
.
51.
Zschiedrich
CP
,
Keidel
V
,
Szurmant
H.
Molecular Mechanisms of Two-Component Signal Transduction
.
Journal of Molecular Biology.
2016
Sep;
428
(
19
):
3752
75
.
52.
Yamamoto
K
,
Hirao
K
,
Oshima
T
,
Aiba
H
,
Utsumi
R
,
Ishihama
A.
Functional Characterization in Vitro of All Two-component Signal Transduction Systems from Escherichia coli
.
Journal of Biological Chemistry.
2005
Jan;
280
(
2
):
1448
56
.
53.
Wang
S.
Bacterial Two-Component Systems: Structures and Signaling Mechanisms.
In: Protein Phosphorylation in Human Health
.
InTech
;
2012
.
54.
Igarashi
M
,
Watanabe
T
,
Hashida
T
,
Umekita
M
,
Hatano
M
,
Yanagida
Y
, et al
Waldiomycin, a novel WalK-histidine kinase inhibitor from Streptomyces sp. MK844-mF10
.
The Journal of Antibiotics.
2013
Aug 1;
66
(
8
):
459
64
.
55.
Francis
S
,
Wilke
KE
,
Brown
DE
,
Carlson
EE
.
Mechanistic insight into inhibition of two-component system signaling
.
MedChemComm.
2013
;
4
(
1
):
269
77
.
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