TABLE III:
Structure of HK inhibitors and their inhibitory activity on HK proteins.
| Structure | Synthesis | TCS | IC50 (μM) | Mechanism of inhibition | Antibacterial activity MIC (μg/ml) |
|
|---|---|---|---|---|---|---|
| A) Isothiazolones | ||||||
 |
NO | AlgR2/ AlgR1 | 1-252 | -Autophosphrylation of AlgR2 -Activity of algD promoter -Phosphorylation of AlgR1 |
Data not shown | |
 |
NO | AlgR2/ AlgR1 | 1-252 | - Autophosphrylation of AlgR2 -Phosphorylation of AlgR1 |
Data not shown | |
| A) Imidazoliums | ||||||
 |
NO | AlgR2/ AlgR1 | 1-252 |
-DNA-binding of AlgR1 -Activity of algD promoter -Autophosphorylation of CheA, NRII and KinA |
Data not shown | |
 |
NO | AlgR2/ AlgR1 | 1-252,53 | -Autophosphorylation of CheA, NRII and KinA | Not determined | |
 |
✓ | WalK/WalR | 6.655 | -Autophosphorylation of multiple HK : EnvZ, PhoQ, BvgS, EvgS and WalK | 3 0.39 0.78 1.56 3.12 0.39 0.39 |
(E. coli)54 (S. aureus)54 (MRSA)54 (S. pneumoniae)54 (PRSP)54 (E. faecalis)54 (VRE)54 |
| B) Trityles | ||||||
 |
✓ | KinA/Spo0F | 556,57 1.658 |
-ATP-competitive -Autophosphorylation of KinA |
1-2 2 1-2 2 1 |
(S. aureus)58
(MRSA)58 (PRSP)58(E. faecalis)58 (VRE)58 |
 |
✓ | KinA/Spo0F | 656,57 | Mechanism was not described | Not determined | |
| C) Benzoxazines | ||||||
 |
✓ | KinA/Spo0F | 959 | Mechanism was not described | 2 4 to 128 |
Gram-positive strains59 Gram-negative strains59 |
 |
✓ | KinA/Spo0F | 1159 | Mechanism was not described | Not determined | |
 |
✓ | KinA/Spo0F | 1359 | Mechanism was not described | 2 | (S. aureus)61 |
| D) Salicylanilides | ||||||
 |
✓ | KinA/Spo0F | 3.865 | -Autophosphorylation of KinA | 1 2 1 1 |
(S. aureus)65
(MRSA)65 (E. faecalis)65 (VRE)65 |
 |
✓ | KinA/Spo0F | 4565 | -Autophosphorylation of KinA | 0.5 0.25 0.5 0.5 |
(S. aureus)65
(MRSA)65 (E. faecalis)65 (VRE)65 |
 |
✓ | KinA/Spo0F | 4.865 | -Autophosphorylation of KinA | 1 1 2 2 |
(S. aureus)66 (MRSA)66 (E. faecalis)66 (E. faecium)66 |
 |
✓ | KinA/Spo0F | 2265 | -Autophosphorylation of KinA | 1 0.25 0.5 0.5 |
(S. aureus)66
(MRSA)66 (E. faecalis)66 (E. faecium)66 |
 |
✓ | KinA/Spo0F | 2.866 | -Autophosphorylation of KinA | 16 16 16 16 |
(S. aureus)66 (MRSA)66 (E. faecalis)66 (E. faecium)66 |
 |
✓ | KinA/Spo0F | 6.366 | -Autophosphorylation of KinA | 8 8 8 32 |
(S. aureus)66
(MRSA)66 (E. faecalis)66 (E. faecium)66 |
| E) Diaryl triazoles | ||||||
 |
✓ | KinA/Spo0F NRII/NRI |
867 2867 |
Mechanism was not described | >64 | Gram-positive strains67 |
 |
✓ | KinA/Spo0F NRII/NRI |
1667 6567 |
Mechanism was not described | 0.25-1 | Gram-positive strains67 |
| F) 6-oxa isosteres | ||||||
 |
✓ | KinA/Spo0F NRII/NRI |
2.270 5.070 |
-Autophosphorylation of KinA | >64 >32 4 4 |
(S. aureus)70
(MRSA)70 (E. faecalis)70 (E. faecium)70 |
 |
✓ | KinA/Spo0F NRII/NRI |
3.070 1.570 |
-Autophosphorylation of KinA | >128 128 8 8 |
(S. aureus)70
(MRSA)70 (E. faecalis)70 (E. faecium)70 |
 |
✓ | KinA/Spo0F NRII/NRI |
4.470 1770 |
-Autophosphorylation of KinA | 8 8 8 8 |
(S. aureus)70
(MRSA)70 (E. faecalis)70 (E. faecium)70 |
| G) Zerumbones | ||||||
 |
NO | WalK/WalR | -71 | Mechanism was not described | Not determined | |
 |
✓ | WalK/WalR (E) WalK/WalR (E/Z) |
63.573 75058 |
-Autophosphorylation of YycG | 62.5 | (B. subtilis)73 |
 |
✓ | WalK/WalR | 43.974 | -Autophosphorylation of WalK | 100 50 |
(MRSA)74 (VRE)74 |
| H) Indoles | ||||||
 |
NO | KinA/Spo0F | 3175 | Mechanism was not described |
1 0.5 1 0.5 |
(S. aureus)75 (MRSA)75 (E. faecalis)75 (E. faecium)75 |
 |
NO | KinA/Spo0F | 7.775 | Mechanism was not described | 4 4 4 4 |
(S. aureus)75 (MRSA)75 (E. faecalis)75 (E. faecium)75 |
| H) Benzimidazoles | ||||||
 |
✓ | KinA/Spo0F | 4275 | Mechanism was not described | 8 16 16 16 |
(S. aureus)75 (MRSA)75 (E. faecalis)75 (E. faecium)75 |
 |
✓ | KinA/Spo0F | 1775 | Mechanism was not described | 4 16 16 16 |
(S. aureus)75 (MRSA)75 (E. faecalis)75 (E. faecium)75 |
 |
✓ | KinA/Spo0F | 1275 | Mechanism was not described | 1 2 2 1 |
(S. aureus)75 (MRSA)75 (E. faecalis)75 (E. faecium)75 |
 |
✓ | KinA/Spo0F | 675 | Mechanism was not described | 1 1 2 2 |
(S. aureus)75 (MRSA)75 (E. faecalis)75 (E. faecium)75 |
 |
✓ | KinA/Spo0F | 1075 | Mechanism was not described | 1 1 1 1 |
(S. aureus)75 (MRSA)75 (E. faecalis)75 (E. faecium)75 |
 |
✓ | KinA/Spo0F | 1075 | Mechanism was not described | Not determined | |
| H) Benzoxazoles | ||||||
 |
✓ | KinA/Spo0F | 1475 | Mechanism was not described | 1 1 1 1 |
(S. aureus)75 (MRSA)75 (E. faecalis)75 (E. faecium)75 |
 |
✓ | KinA/Spo0F | 15.475 | Mechanism was not described | 2 2 2 1 |
(S. aureus)75 (MRSA)75 (E. faecalis)75 (E. faecium)75 |
| I) Sulfonamides | ||||||
 |
✓ | QseC/ QseB | -77 | Receptor antagonist interfering with signal binding of QseC | No antimicrobial activity but inhibition of virulence | |
| J) Thiazolidiones | ||||||
 |
NO | WalK/WalR | 2980 | -Autophosphorylation of WalK (Binds to HK) |
13 13 51 |
(S. epidermidis)80 (S. aureus)80 (S. pyogenes)80 |
 |
NO | WalK/WalR | 1480 | -Autophosphorylation of WalK (Binds to HK) |
4 4 1 |
(S. epidermidis)80 (S. aureus)80 (S. pyogenes)80 |
 |
✓ | WalK/WalR | 34.883 | -Autophosphorylation of WalK | 6.2 3.1-6.2 |
(S. epidermidis)83 (S. aureus)83 |
 |
✓ | WalK/WalR | 22.183 | -Autophosphorylation of WalK | 3.1 3.1-6.2 |
(S. epidermidis)83 (S. aureus)83 |
 |
✓ | WalK/WalR | 12.684 | -Autophosphorylation of WalK | 0.93 1.90 3.8 |
(S. epidermidis)84 (S. epidermidis)84 (S. aureus)84 |
| K) Thiophenes | ||||||
 |
✓ |
WalK/WalR PhoR/PhoP ResE/ResD |
196.987 122.687 124.387 |
-Autophosphorylation of WalK -ATP-competitve |
7 16 7 10 16 10 32 32 32 |
(B. subtilis)87 (S. aureus)87 (B. anthracis)87 (S. pyogenes)87 (S. agalactiae)87 (L. monocytogenes)87 (E. faecalis)87 (S. enterica)87 (E. coli)87 |
 |
✓ |
WalK/WalR PhoR/PhoP ResE/ResD |
52.887 13.187 89.387 |
-Autophosphorylation of WalK -ATP-competitve |
7 32 7 16 32 32 >64 32 32 |
(B. subtilis)87 (S. aureus)87 (B. anthracis)87 (S. pyogenes)87 (S. agalactiae)87 (L. monocytogenes)87 (E. faecalis)87 (S. enterica)87 (E. coli)87 |
 |
✓ |
WalK/WalR PhoR/PhoP ResE/ResD |
181.187 21.387 52.287 |
-Autophosphorylation of WalK -ATP-competitve |
No antibacterial activity | |
 |
✓ |
WalK/WalR PhoR/PhoP ResE/ResD |
80.187 11.387 243.987 |
-Autophosphorylation of WalK -ATP-competitve |
No antibacterial activity | |
 |
✓ |
WalK/WalR PhoR/PhoP ResE/ResD |
134.487 1.6387 102.387 |
-Autophosphorylation of WalK -ATP-competitve |
No antibacterial activity | |
 |
✓ |
WalK/WalR PhoR/PhoP ResE/ResD |
78.387 44.087 32.887 |
-Autophosphorylation of WalK -ATP-competitve |
No antibacterial activity | |
 |
✓ |
WalK/WalR PhoR/PhoP ResE/ResD |
121.387 33.387 40.387 |
-Autophosphorylation of WalK -ATP-competitve |
No antibacterial activity | |
 |
✓ |
WalK/WalR PhoR/PhoP ResE/ResD |
145.687 46.187 20.387 |
-Autophosphorylation of WalK -ATP-competitve |
No antibacterial activity | |
| L) Adenines | ||||||
 |
NO | HK853 | 49.688 | -Autophosphorylation of HK853 -ATP-competitive |
Not determined | |
 |
NO | HK853 | 95.388 | -Autophosphorylation of HK853 -ATP-competitive |
Not determined | |
 |
NO | HK853 | 14588 | -Autophosphorylation of HK853 -ATP-competitive |
Not determined | |
 |
NO | HK853 | 13188 | -Autophosphorylation of HK853 -ATP-competitive |
Not determined | |
 |
✓ | HK853 | 7.389,91 | -Autophosphorylation of HK853 -ATP-competitive |
Not determined | |
| M) Diaryl oxazoles | ||||||
 |
NO | CckA PhoP/PhoQ |
7.392 73 |
Mechanism was not described | 17-35 >140 >140 |
(E. coli)92 (C. crescentus)92 (B. subtilis)92 |
| M) Diaryl pyrazoles | ||||||
 |
NO | CckA PhoP/PhoQ |
2892 992 |
Mechanism was not described | 13-26 53-79 40 |
(E. coli)92 (C. crescentus)92 (B. subtilis)92 |
 |
✓ | CckA PhoP/PhoQ |
12.392 6692 |
-Autophosphorylation of CckA and PhoQ -ATP-competitve |
12-25 74 50-74 |
(E. coli)92 (C. crescentus)92 (B. subtilis)92 |
 |
✓ | CckA PhoP/PhoQ |
17.592 4592 |
-Autophosphorylation of CckA and PhoQ -ATP-competitve |
11-23 68 45 |
(E. coli)92 (C. crescentus)92 (B. subtilis)92 |
 |
✓ | CckA PhoP/PhoQ |
11.292 3592 |
-Autophosphorylation of CckA and PhoQ -ATP-competitve |
27 81 40-54 |
(E. coli)92 (C. crescentus)92 (B. subtilis)92 |
| N) Miscellaneous | ||||||
| N) Thienopyridine | ||||||
 |
NO |
HpkA/DrrA WalK/WalR EnvZ/OmpR VanS/VanR |
5.593 13.293 26.893 103.893 |
-Autophosphorylation of HpkA, WalK, EnvZ and VanS -ATP-competitve |
>256 | (S. pneumoniae, E. faecium, E. faecalis, H. influenza,
E. coli)93 |
| N) WalKmycins | ||||||
 |
NO | WalK/WalR (Bs) WalK/WalR (Sa) |
1.696 5.796 |
-Autophosphorylation of WalK by binding cytoplasmic domain | 0.39 0.2 0.39 6.25 0.39 |
(B. subtilis)96 (S. aureus)96 (MRSA)96 (E. faecalis)96 (VRE)96 |
 |
NO |
VicK/VicR CiaH/CiaR LiaS/LiaR |
2.8797 4.8797 5.6397 |
-Autophosphorylation of VicK, CiaH, LiaS by binding cytoplasmic domain | 0.06-0.25 0.06-1 2-8 8-16 0.13-0.25 0.25-1 |
(S. aureus)97
(B. subtilis)97 (E. faecalis)97 (E. faecium)97 (S. pneumoniae)97 (S. pyogenes)97 |
| N) Signermycin | ||||||
 |
NO |
WalK/WalR (Bs) WalK/WalR (Sa) WalK/WalR (Ef) WalK/WalR (Sm) |
4398 3798 6198 6298 |
-Autophosphorylation of WalK -Binding the dimerization domain of WalK |
3.13 3.13 6.25 6.25 3.13 |
(B. subtilis)98
(S. aureus)98 (E. faecalis)98 (S. mutans)98 (MRSA)98 (VRE)98 |
| N) Waldiomycin | ||||||
 |
NO |
WalK/WalR (Bs) WalK/WalR (Sa) WalK/WalR (Ef) WalK/WalR (Sm) |
10.299,100 8.899,100 9.2100 25.8100 |
-Autophosphorylation of WalK -Targeting the dimerization domain of WalK |
8 8-16 16 128 |
(B. subtilis)99
(S. aureus)99 (MRSA)99 (E. faecalis)99 |
| N) Phenol | ||||||
 |
NO | PhoR/PhoB (Ec) PhoR/PhoP (Sa) |
16102,103 212102,103 |
-Autophosphorylation of PhoR -ATP-competitive |
8-16 1-16 8 16 |
(S. aureus)102,103 (S. epidermidis)102,103 (S. suis)102,103 (S. pneumoniae)102,103 |
| N) Benzothiazole | ||||||
 |
NO | HK853 VicK/VicR |
1.2188 7588 |
-Autophosphorylation of HK853 and VicK -ATP-competitive |
32-64 49-64 |
(E. coli)88(B. subtilis)88 |
 |
NO | HK853 VicK/VicR |
7.1588 61888 |
-Autophosphorylation of HK853 and VicK -ATP-competitive |
128 293 |
(E. coli)88 (B. subtilis)88 |
 |
NO | HK853 | 8.388,91,104 | Mechanism was not described Reduce production of virulence factors |
No antibacterial activity | |
 |
NO | HK853 | 1.5688,91,104 | Mechanism was not described Reduces production of virulence factors |
No antibacterial activity | |
| N) 5H-Pyrrolo[2,3-b]pyrazine | ||||||
 |
NO | HK853 | 23.7105 | Mechanism was not described | Not determined | |