Antibacterial Agents that Inhibit Histidine Protein Kinase YycG of Bacillus subtilis

Yamamoto, Kaneyoshi; Kitayama, Takashi; Minagawa, Shu; Watanabe, Takafumi; Sawada, Seiji; Okamoto, Tadashi; Utsumi, Ryutaro

doi:10.1271/bbb.65.2306

Cited by 64 publications

(45 citation statements)

References 21 publications

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“…[4][5][6][7][8] As such, the WalK/WalR system constitutes an attractive target for the development of novel antimicrobial compounds, as inhibitors targeting WalK or WalR would be expected to have a bactericidal effect toward a broad range of major Grampositive pathogens. Previously, a number of HK inhibitors have been identified, [9][10][11][12] but these studies did not conclusively show a direct relationship between cell death and HK inhibition rather than some other uncharacterized nonspecific effect. However, structure-based virtual screening of compounds potentially targeting the kinase activity of S. epidermidis WalK found several to be active against not only S. epidermidis but also S. aureus, S. aureus and S. mutans.…”

Section: Introductionmentioning

confidence: 99%

Novel antibacterial compounds specifically targeting the essential WalR response regulator

et al. 2010

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The WalK/WalR (YycG/YycF) two-component system, which is essential for cell viability, is highly conserved and specific to low-GC percentage of Gram-positive bacteria, making it an attractive target for novel antimicrobial compounds. Recent work has shown that WalK/WalR exerts an effect as a master regulatory system in controlling and coordinating cell wall metabolism with cell division in Bacillus subtilis and Staphylococcus aureus. In this paper, we develop a high-throughput screening system for WalR inhibitors and identify two novel inhibitors targeting the WalR response regulator (RR): walrycin A (4-methoxy-1-naphthol) and walrycin B (1,6-dimethyl-3-[4-(trifluoromethyl)phenyl]pyrimido [5,4-e][1,2,4]triazine-5,7-dione). Addition of these compounds simultaneously affects the expression of WalR regulon genes, leading to phenotypes consistent with those of cells starved for the WalK/WalR system and having a bactericidal effect. B. subtilis cells form extremely long aseptate filaments and S. aureus cells form large aggregates under these conditions. These results show that walrycins A and B are the first antibacterial agents targeting WalR in B. subtilis and S. aureus.

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Section: Introductionmentioning

confidence: 99%

Novel antibacterial compounds specifically targeting the essential WalR response regulator

et al. 2010

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“…Walkmycin B was concentrated in vacuo to give 99.7 mg of brownish yellow oil. The crude oil was further purified by crystallization in a mixture solvent of 13 C NMR, and physico-chemical properties of walkmycin B were very similar to those of BE40665 A. 23 As walkmycin B is not stable in DMSO and acetone, we could not compare the chemical shifts of 1 H, 13 C NMR and the specific rotation of walkmycin B with those of BE40665 A.…”

Section: Purification Of Walkmycin Bmentioning

confidence: 99%

“…The crude oil was further purified by crystallization in a mixture solvent of 13 C NMR, and physico-chemical properties of walkmycin B were very similar to those of BE40665 A. 23 As walkmycin B is not stable in DMSO and acetone, we could not compare the chemical shifts of 1 H, 13 C NMR and the specific rotation of walkmycin B with those of BE40665 A. However, a series of two-dimensional NMR and nuclear overhauser enhancement spectroscopy analyses indicated the structure of BE40665 A.…”

Section: Purification Of Walkmycin Bmentioning

confidence: 99%

“…NH125 is a non-specific HK inhibitor. 13 Figure 4 Effect of walkmycin B on cell morphology. After B. subtilis 168 was incubated in the absence (photo 1) or presence of walkmycin B (photo 2, 0.25 mg ml À1 ; photo 3, 0.5 mg ml À1 ; photo 4, 1.0 mg ml À1 ) in LB for 4 h at 37 1C, it was observed under a microscope (Â800).…”

Section: Hk Inhibitory Activitymentioning

confidence: 99%

“…13 Imidazole derivatives had antibacterial activity in drug-resistant S. aureus, E. faecalis and S. pneumoniae, as well as in B. subtilis, with MICs of 0.39-6.25 mg ml À1 . However, the inhibitors have caused structural alteration of HK leading non-specifically to aggregation.…”

Section: Introductionmentioning

confidence: 99%

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Walkmycin B targets WalK (YycG), a histidine kinase essential for bacterial cell growth

et al. 2010

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The WalK (a histidine kinase)/WalR (a response regulator, aka YycG/YycF) two-component system is indispensable in the signal transduction pathway for the cell-wall metabolism of Bacillus subtilis and Staphylococcus aureus. The inhibitors directed against WalK would be expected to have a bactericidal effect. After we screened 1368 culture broths of Streptomyces sp. by a differential growth assay, walkmycin A, B and C, which were produced by strain MK632-100F11, were purified using silica-gel column chromatography and HPLC. In this paper, the chemical structure of the major product (walkmycin B) was determined to be di-anthracenone (C 44 H 44 Cl 2 O 14 ), which was very similar to BE40665A. MICs of walkmycin B against B. subtilis and S. aureus were 0.39 and 0.20 lg ml À1 , and IC 50 measurements against WalK were 1.6 and 5.7 lM, respectively. To clarify the affinity between WalK and walkmycin B, surface plasmon resonance was measured to obtain the equilibrium dissociation constant, K D1 , of 7.63 lM at the higher affinity site of B. subtilis WalK. These results suggest that walkmycin B inhibits WalK autophosphorylation by binding to the WalK cytoplasmic domain.

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Bacterial protein kinase inhibitors

Kurosu

Eeshwaraiah

2010

Drug Development Research

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Protein kinases have become the second most important group of drug targets for the pharmaceutical industry next to G-protein-coupled receptors. Thus, over the past decade, a significant number of small molecules have been generated for protein kinase drug optimization programs. The vast majority of kinase inhibitors target the ATP binding site of the enzyme; however, the poor protein kinase selectivity of ATP-competitive protein kinase inhibitors (PKIs) limits their use for treating chronic diseases. In contrast, for inhibitors of bacterial signal transduction systems targeting bacterial kinase(s), there are no such selectivity requirements as long as the inhibitor does not act on any human kinases at the effective concentrations for killing bacteria in vivo. Protein phosphorylation in bacteria is performed by twocomponent signal transduction systems (2CSTSs) and eukaryotic-like serine/threonine kinases or bacterial tyrosine kinases. Recently, a large number of studies of protein kinases essential for sustaining bacterial growth and kinases required for virulence have been reported. Thus, bacterial protein kinases offer considerable potential as new drug targets. To identify bacterial PKIs, large chemical libraries of ATPcompetitive inhibitors developed for eukaryotic protein kinases are an invaluable asset. This manuscript reviews progress on the development of prokaryotic protein kinase inhibitors. Drug Dev Res 71:168-187, 2010.

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Antibacterial Agents that Inhibit Histidine Protein Kinase YycG of Bacillus subtilis

Cited by 64 publications

References 21 publications

Novel antibacterial compounds specifically targeting the essential WalR response regulator

Novel antibacterial compounds specifically targeting the essential WalR response regulator

Walkmycin B targets WalK (YycG), a histidine kinase essential for bacterial cell growth

Bacterial protein kinase inhibitors

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