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Two Component System As Drug Targets in Pathogenic Bacteria

Two-component signal transduction systems (TCS) are used by bacteria to sense and respond to environmental signals and control virulence factors. TCS involve a histidine kinase sensor that phosphorylates a response regulator. Inhibiting essential or non-essential TCS that control virulence could provide new antibiotics with less resistance development. Several inhibitors have been identified for specific TCS that control virulence in pathogenic bacteria like Pseudomonas, Salmonella, and Staphylococcus. Developing more TCS inhibitors requires improving selectivity and targeting other conserved domains.

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Shveta Jaishankar Iyer
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119 views

Two Component System As Drug Targets in Pathogenic Bacteria

Two-component signal transduction systems (TCS) are used by bacteria to sense and respond to environmental signals and control virulence factors. TCS involve a histidine kinase sensor that phosphorylates a response regulator. Inhibiting essential or non-essential TCS that control virulence could provide new antibiotics with less resistance development. Several inhibitors have been identified for specific TCS that control virulence in pathogenic bacteria like Pseudomonas, Salmonella, and Staphylococcus. Developing more TCS inhibitors requires improving selectivity and targeting other conserved domains.

Uploaded by

Shveta Jaishankar Iyer
Copyright
© Attribution Non-Commercial (BY-NC)
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PPTX, PDF, TXT or read online on Scribd
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Two Component signal transduction as

potential drug targets in pathogenic


bacteria
Yasuhiro Gotoh, Yoko Eguchi, Takafumi Watanabe, Sho Okamoto,Akihiro Doi and
Ryutaro Utsumi
Curr Opin Microbiol, 2010, 13:232–239
Introduction
• Bacteria respond different
environment signals
• These signals can be pH,
Nutrient level, Redox state,
Osmotic pressure, Quorum
signals and antibiotics
• For this they use a two
component signal
transduction system (TCS)
• TCS is absent in
mammals(including Homo
sapiens)
• Hence these TCS can be
targeted for drugs
Classic TCS
Has
- Sensory kinase( Histidine
kinase)(HK)
Autophosphorylated on conserved
His residue.
Phosphoryl group transferred to RR.
- Response regulator (RR)
• Phosphorylated by HK at Asp
residue.
• Phosphorylated RR binds to
upstream regulatory region of
pathogenic genes and controls
their expression.
• Dephosphorylated by HK. http://syntheticmicrobe.bio.lmu.de/research/signal_transdu
ct/index.html
Molecular Mechanism of specific TCS
• TCS are involved in regulation 2 gene types
- genes required for cell growth and is
essential
- genes required for virulence in pathogenic
bacteria and are not essential.
• These portions have the potential to serve as
effective drug targets

http://www.esrf.eu/news/spotlight/spotlight105/
Essential TCS
• WalK/WalR TCS
Required for growth of pathogenic bacteria
such as B. subtilis, S. aureus, E. faecalis, L.
monocytogenes, S. pneumoniae, S. mutans,
S. pyogenes
Mostly involved in cell wall metabolism,
biofilm formation etc.
Inhibitors of WalK/WalR TCS
• Inhibitors of this pathway identified by
differential growth assay and
homodimerization assay. They were
walkmycin B and walrycin B respectively

• Other inhibitors were thiazolidinone


derivatives against S. epidermidis
identified by virtual screening of small
molecule lead-compound library.
Non Essential TCS
• Virulence factors such as toxins, proteases, lipase
are required for host invasion, other properties
required are motility, adherence to host,
colonization.
• These factors and properties are controlled by TCS
where the host environmental factors activate these
systems.
E.g. P. aeroginosa has 64 HKs and 72 RRs out of which
19 are involved in virulence and antibiotic
resistance
QseC/QseB
• E.Coli [EHEC] causative agent of
bloody diarrhea and hemolytic-
uremic syndrome use this TCS for
virulence.
• By quorum sensing, chemical
autoinducer (AI-3)is produced that
rapid induce virulence gene LEE.
• LEE gene expressed during high
concentrations of human hormones
epinephrine and norepinephrine.
• QseC/QseB TCS regulates flagella
regulon and LEE gene shiga toxin.
• Inhibitor LED209 supressed
pathogenic genes LEE1,flhDC and
stx2A and inhibited auto
phosphorylation of QseC
AgrC / AgrA
• S. aureus an oppurtunistic
pathoges has its virulence
controlled by TCS AgrC/AgrA
that regulates virulence factors
• AgrD is an AIP [autoinducing
cyclic thiolactone peptides]
that is processed by AgrB that
is present in the cell
membrane.
• Processed AIP are sensors for
AgrC/AgrA TCS.
• Inhibitors include noncognate
AIPs and apolipoprotein.
FsrC/FsrA
• Multiple antibiotic resistant E. faecalis causes
opportunistic nosocomial infections.
• Virulence factors gelatinase and serine protease coded
by genes gelE and sprE are present in the same operon
• They depend on concentration of GBAP ( gelatinase
biosynthesis-activating pheromone) i.e secreted
outside the cell
• GBAP production positively controlled by FsrC/FsrA TCS
that in turn trigger FsrC/FsrA controlling expression of
genes fsrBDC and gelE-sprE.
• Inhibitors from mycetal extracts were identified,
Siamycin I (peptide).
GacS/GacA
• P. aeruginosa depends on
this TCS for their virulence in
nosocomial infections.
• Virulence factors like acyl
homoserine
lactones,pyocyanin,lipase,ela
stase etc are involved whose
transcription is indirectly
controlled by GacS/GacA TCS
• E.carotovora causes soft rot
disease in plants when there
is GacS/GacA mediated
production of rsmB gene
product
Environmental microbiology –Ralph mitchell
PhoQ/PhoP
• Regulates Salmonella’s ability to invade epithelial
cells, survive in phagocytic cells and resist AMPs
• PhoQ sensor detects extracellular Mg+2
concentration and mediates expression of 3% of
salmonella genes by PhoP
• Inhibitors include GHL inhibitors such as Radicicol
that bind to ATP binding Bergerat fold.
• This TCS is also present in E. caratovora called
PehS/PehR that regulates endopolygalacturonase
required for virulence.
CorS/CorR HrpX/HrpY
E. amylovora’s Type III secretion system
P.Syringae caused chlorosis due to (T3SS) controlled by this system and
phytotoxin coronatine detected by low pH, low nutrient level, low
temperature.
Inhibitor identified – p – coumaric acid
Conclusion
• Sensory domains are the main drug targets in TCS
• Development of drugs targeting other conserved
domains to act on pathways involving multiple TCSs
• HK inhibitors showed poor selectivity of TCS and
damaged membranes of cells
• TCS inhibitors to be developed covering their broad
range and has to be highly specific to them.
• These inhibitors can be new antibiotics against
multidrug resistant pathogens and antivirulence
agents for pathogens without essential TCS.

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