Study on &lt;i&gt;in vivo&lt;/i&gt; effects of bacterial histidine kinase inhibitor, Waldiomycin, in &lt;i&gt;Bacillus subtilis&lt;/i&gt; and &lt;i&gt;Staphylococcus aureus&lt;/i&gt;

Fakhruzzaman, Md.; Inukai, Yoichi; Yanagida, Yohei; Kino, Hirokazu; Igarashi, Masayuki; Eguchi, Yawara; Utsumi, Ryutaro

doi:10.2323/jgam.61.177

Cited by 18 publications

(10 citation statements)

References 38 publications

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“…Despite this general attitude, there has been certain progress in harnessing bacterial signalling systems to elicit favourable responses. The natural inclination is to search for compounds such as (waldiomycin and signermycin B) that target the essential genes involved in signal transduction, e.g., (in Gram-positive bacteria) histidine kinase WalK (YycG), and to measure success by the efficiency of killing B. subtilis, Staphylococcus aureus and Streptococcus mutans (Watanabe et al, 2012;Fakhruzzaman et al, 2015). However, managingor even preventingdisease does not necessarily require eradication of the bacteria.…”

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confidence: 99%

What bacteria want

Galperin

2018

Environmental Microbiology

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Bacterial signal transduction systems are responsible for sensing environmental cues and adjusting the cellular behaviour and/or metabolism in response to these cues. They also monitor the intracellular conditions and the status of the cell envelope and the cytoplasmic membrane and trigger various stress responses to counteract adverse changes. This surveillance involves several classes of sensor proteins: histidine kinases; chemoreceptors; membrane components of the sugar phosphotransferase system; adenylate, diadenylate and diguanylate cyclases and certain cAMP, c-di-AMP and c-di-GMP phosphodiesterases; extracytoplasmic function sigma factors and Ser/Thr/Tyr protein kinases and phosphoprotein phosphatases. We have compiled a detailed listing of sensor proteins that are encoded in the genomes of Escherichia coli, Bacillus subtilis and 10 widespread pathogens: Chlamydia trachomatis, Haemophilus influenzae, Helicobacter pylori, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Porphyromonas gingivalis, Rickettsia typhi, Streptococcus pyogenes and Treponema pallidum, and checked what, if anything, is known about their functions. This listing shows significant gaps in the understanding of which environmental and intracellular cues are perceived by these bacteria and which cellular responses are triggered by the changes in the respective parameters. A better understanding of bacterial preferences may suggest new ways to modulate the expression of virulence factors and therefore decrease the reliance on antibiotics to fight infection.

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confidence: 99%

What bacteria want

Galperin

2018

Environmental Microbiology

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“…Identification of compounds that inhibit the activity of two component systems has been mooted as a potential path to find new antibiotics (see for example, Desnottes, 1996;Matsushita and Janda, 2002;Watanabe et al, 2008;Gotoh et al, 2010;Bem et al, 2015). Indeed, one such compound, waldiomycin, which was identified from a screen for kinase inhibitors, has been proposed as a potential treatment of Gram-positive bacterial infections (Igarashi et al, 2013;Fakhruzzaman et al, 2015;Eguchi et al, 2017). Other examples of identified TCS inhibitors are given in Bem et al (2015).…”

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confidence: 99%

The Signaling Molecule Indole Inhibits Induction of the AR2 Acid Resistance System in Escherichia coli

et al. 2020

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Induction of the AR2 acid response system of Escherichia coli occurs at a moderately low pH (pH 5.5) and leads to high levels of resistance to pH levels below 2.5 in the presence of glutamate. Induction is mediated in part by the EvgAS two component system. Here, we show that the bacterial signaling molecule indole inhibits the induction of key promoters in the AR2 system and blocks the development of glutamatedependent acid resistance. The addition of tryptophan, the precursor for indole biosynthesis, had the same effects, and this block was relieved in a tnaA mutant, which is unable to synthesize indole. Expression of a constitutively active EvgS protein was able to relieve the inhibition caused by indole, consistent with EvgS being inhibited directly or indirectly by indole. Indole had no effect on autophosphorylation of the isolated cytoplasmic domain of EvgS. This is consistent with a model where indole directly or indirectly affects the ability of EvgS to detect its inducing signal or to transduce this information across the cytoplasmic membrane. The inhibitory activity of indole on the AR2 system is not related to its ability to act as an ionophore, and, conversely, the ionophore CCCP had no effect on acid-induced AR2 promoter activity, showing that the proton motive force is unlikely to be a signal for induction of the AR2 system.

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“…This motif was further supported by the observation that waldiomycin inhibited other HKs such as ResE and PhoR, which share the characteristic residues in the H-box region with WalK, with comparable IC 50 s. To a lesser extent, waldiomycin also inhibited CitS, which is segregated from the WalK cluster in the phylogenetic analysis of the H-box region sequences of HKs in B. subtilis. Previously, we reported the IC 50 s of waldiomycin against the WalK HKs of B. subtilis, S. aureus, E. faecalis, and Streptococcus mutans (Fakhruzzaman et al, 2015;Igarashi et al, 2013) and showed that waldiomycin is a general WalK inhibitor. In this study, the target of waldiomycin was extended from WalK to other HKs in B. subtilis.…”

Section: Waldiomycin Inhibits Multiple B Subtilis Hks In Vitromentioning

confidence: 99%

“…The extraction of total RNA from B. subtilis 168 and its mutant strains (R377M/R378M/S385A and R377M/R378M/R389M), cultured in the presence or absence of waldiomycin and qRT-PCR, were performed as previously described (Fakhruzzaman et al, 2015). The primers used for qRT-PCR are listed in Table 3.…”

Section: Extraction Of Total Rna and Qrt-pcrmentioning

confidence: 99%

“…Recently, we screened for WalK inhibitors from natural sources using a previously reported method (Watanabe et al, 2012) and isolated and characterized a new antibiotic, waldiomycin (Fakhruzzaman et al, 2015;Igarashi et al, 2013). Waldiomycin is an angucycline antibiotic composed of 1,3-dioxolane-2-carboxylic acid linked to an angucyclic polyketide via a tetraene linker and tetrahydropyran (Igarashi et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of H-box region mutants of WalK inert to the action of waldiomycin in <i>Bacillus subtilis</i>

Kato

Ueda

Oshima

et al. 2017

J. Gen. Appl. Microbiol.

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The WalK/WalR two-component system is essential for cell wall metabolism and thus for cell growth in Bacillus subtilis. Waldiomycin was previously isolated as an antibiotic that targeted WalK, the cognate histidine kinase (HK) of the response regulator, WalR, in B. subtilis. To gain further insights into the action of waldiomycin on WalK and narrow down its site of action, mutations were introduced in the H-box region, a well-conserved motif of the bacterial HKs of WalK. The half-maximal inhibitory concentrations (ICs) of waldiomycin against purified WalK protein with triple substitutions in the H-box region, R377M/R378M/S385A and R377M/R378M/R389M, were 26.4 and 55.1 times higher than that of the wild-type protein, respectively, indicating that these residues of WalK are crucial for the inhibitory effect of waldiomycin on its kinase activity. Surprisingly, this antibiotic severely affected cell growth in a minimum inhibitory concentration (MIC) assay, but not transcription of WalR-regulated genes or cell morphology in B. subtilis strains that harbored the H-box triple substitutions on the bacterial chromosome. We hypothesized that waldiomycin targets other HKs as well, which may, in turn, sensitize B. subtilis cells with the H-box triple mutant alleles of the walK gene to waldiomycin. Waldiomycin inhibited other HKs such as PhoR and ResE, and, to a lesser extent, CitS, whose H-box region is less conserved. These results suggest that waldiomycin perturbs multiple cellular processes in B. subtilis by targeting the H-box region of WalK and other HKs.

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Study on <i>in vivo</i> effects of bacterial histidine kinase inhibitor, Waldiomycin, in <i>Bacillus subtilis</i> and <i>Staphylococcus aureus</i>

Cited by 18 publications

References 38 publications

What bacteria want

What bacteria want

The Signaling Molecule Indole Inhibits Induction of the AR2 Acid Resistance System in Escherichia coli

Characterization of H-box region mutants of WalK inert to the action of waldiomycin in <i>Bacillus subtilis</i>

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