Bacterial Signal Transduction Systems for Environmental Adaptation and Their Inhibitors.

Utsumi, Ryutaro

doi:10.1264/jsme2.2002.1

Cited by 3 publications

(3 citation statements)

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“…It has been reported that overexpression of the regulator EvgA confers MDR to a drug-hypersusceptible E. coli strain which lacks the major multi-drug efflux pump gene, acrB (Nishino & Yamaguchi, 2001a, 2002, and acid resistance to exponentially growing cells (Masuda & Church, 2002). In addition to the up-regulation of the multi-drug efflux genes confirmed in the present study, activation of EvgS also upregulated the acid-resistance-related genes, gadABC, hdeAB, ydeP, ydeO and yhiE (available as supplementary data in Microbiology online at http://mic.sgmjournals.org), as in the EvgA-overexpressed strain (Masuda & Church, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…EvgS is a histidine kinase hybrid sensor, which is composed of an N-terminal periplasmic region and a C-terminal cytoplasmic region that is divided into four domains: linker, transmitter, receiver and output (Hpt) (Perraud et al, 1998). The periplasmic domain of EvgS is involved in signal recognition, ultimately transducing the signal into a transcriptional regulation network via a cascade of phosphorylation (Utsumi, 2002;Utsumi et al, 1994). To date, however, the target genes under the control of EvgAS are still poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli

et al. 2003

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A constitutively active mutant of histidine kinase sensor EvgS was found to confer multi-drug resistance (MDR) to an acrA-deficient Escherichia coli, indicating the relationship between the two-component system EvgAS and the expression of the MDR system. The observed MDR also depended on an outer-membrane channel, TolC. Microarray and S1 mapping assays indicated that, in the presence of this constitutive mutant EvgS, the level of transcription increased for some MDR genes, including the drug efflux genes emrKY, yhiUV, acrAB, mdfA and tolC. Transcription in vitro of emrK increased by the addition of phosphorylated EvgA. Transcription activation of tolC by the activated EvgS was, however, dependent on both EvgAS and PhoPQ (Mg 2+ -responsive two-component system), in agreement with the presence of the binding site (PhoP box) for the regulator PhoP in the tolC promoter region. Transcription in vitro of yhiUV also appears to require an as-yet-unidentified additional transcriptional factor besides EvgA. Taken together we propose that the expression of the MDR system is under a complex regulatory network, including the phosphorylated EvgA serving as the master regulator.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli

et al. 2003

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“…Essential CSTSs have been identified; for example, mtrA in M. tuberculosis, yycF/ yycG in S. pneumonia, S. aureus, and B. subtilis. The YycF/YycG 2CSTSs are conserved among other Grampositive bacteria, and thus considered a promising target for Gram-positive pathogens [Utsumi, 2002]. Extensive medicinal chemistry efforts to improve physicochemical properties of promising lead molecules (i.e., summarized in Table 1) and to develop novel 2CSTS inhibitors are expected in the next decade.…”

Section: Discussionmentioning

confidence: 99%

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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Introduction to Bacterial Signal Transduction Networks

Eguchi

Utsumi

Advances in Experimental Medicine and Biology

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Transcriptional analysis using a DNA microarray is an extremely efficient method for analyzing two-component signal transduction networks. Here we introduce three such networks in Escherichia coli that were clarified using a DNA microarray: a PhoQ/PhoP system that senses extracellular Mg2+ and controls the gene expression for adaptation to environmental Mg2+ deprivation (Mg2+ stimulon); an EvgS/EvgA signal transduction system that activates expression of multiple drug efflux pumps and acid resistance genes; and a signal transduction cascade between EvgS/EvgA and PhoQ/PhoP.

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Bacterial Signal Transduction Systems for Environmental Adaptation and Their Inhibitors.

Cited by 3 publications

References 39 publications

Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli

Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli

Bacterial protein kinase inhibitors

Introduction to Bacterial Signal Transduction Networks

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