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. Author manuscript; available in PMC: 2020 Feb 14.
Published in final edited form as: Environ Microbiol. 2018 Oct 25;20(12):4221–4229. doi: 10.1111/1462-2920.14398

What bacteria want

Michael Y Galperin 1
PMCID: PMC7020242  NIHMSID: NIHMS1555427  PMID: 30187651

Summary

Bacterial signal transduction systems are responsible for sensing environmental cues and adjusting the cellular behavior 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 ten 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 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 expression of virulence factors and therefore decrease the reliance on antibiotics to fight infection.

In a 2000 Hollywood movie, a self-centered male executive gains the ability to hear what women are thinking, which causes him to re-evaluate his attitudes and adjust his behavior (https://www.wikipedia.org/wiki/What_Women_Want). By studying bacterial signal transduction pathways, microbiologists are trying to acquire a somewhat similar skill: to be able to figure out what the objects of our attention are looking for and, accordingly, how we could make them happy and possibly avoid confrontation.

Similarly to the idea of the ‘bacterial IQ’, introduced several years ago (Galperin, 2005; Galperin et al., 2010), this approach may be perceived as misguided anthropomorphism. However, despite obvious mechanistic differences, sensory logics of bacteria and humans show certain parallels. In bacterial chemotaxis, the sensed compounds are traditionally referred to as attractants and repellents (Szurmant and Ordal, 2004; Hazelbauer, 2012). In diauxic growth, carbon sources are described as ‘preferred’ and ‘non-preferred’ (Monod, 1942; Deutscher, 2008; Buffing et al., 2018). Remarkably, chemotactic attractants are not necessarily the best nutrients, the nature of the signaling response is much more complex than that. Hence, the question ‘What do bacteria want?’ seems totally legitimate.

Answering this question becomes ever more important as the pool of effective antibiotics continues to shrink, limiting our choices to counteract bacterial infections. Although the first recipe of using mold extract to cure disease dates back almost 4,000 years (see Galperin and Koonin, 1999), the wide use of antibiotics in the past 75 years has led to the emergence of multidrug-resistant bacteria. In an amazing combination of Darwinian selection (survival of the fittest, i.e. the most resistant, strains) with prokaryotic “altruistic” gene sharing, resistance to commonly used antibiotics is spreading like a wildfire (actually, much faster than that). The recent proliferation of the colistin resistance gene mcr-1 (Wang et al., 2018) offers just the latest example of this phenomenon. The remarkable success in finding evolution-proof antibacterials (Ling et al., 2015; Bell and MacLean, 2018) might give us a reprieve for the near future. However, another question of using broad-spectrum antibiotics remains: how smart is it to try killing most bacteria in one’s body just to get rid of several bad actors? Development of new vaccines should help (Rappuoli et al., 2017), but the only ready solution to this conundrum is to understand what bacteria really want and how could we dissuade them from harming their human (animal) hosts.

It helps that now we have available the human genome sequence and genome sequences of most bacterial pathogens. In contrast to humans, whose cells encode more than 600 protein kinases and ca. 800 G-protein coupled receptors (GPCRs), bacteria have far fewer signaling proteins, whose functions are gradually being uncovered.

About 20 years ago, Céline Fabret, Victoria Feher and James Hoch published a minireview on two-component signal transduction in Bacillus subtilis with a provocative subtitle “How one organism sees its world”. Making use of the just-finished complete genome sequence of B. subtilis strain 168, they examined 36 histidine kinases (HKs) and 35 response regulators (RRs) encoded in this genome and classified them into several groups based on the organization of the conserved motifs surrounding phosphoacceptor His residues in HKs and Asp residues in RRs (Fabret et al., 1999). The same year, a joint paper from Saier and Stülke labs provided a careful analysis of the components of the phosphoenolpyruvate:sugar phosphotransferase system (PTS) encoded in B. subtilis (Reizer et al., 1999), while we presented an account of the c-di-GMP-related GGDEF, EAL and HD-GYP domains in several model genomes (Galperin et al., 1999). These and other papers paved the way to the knowledge-based annotation of the signaling machineries in model organisms, such as Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa, Vibrio cholerae, and many others. Several groups independently compiled comprehensive lists of the signaling proteins encoded in bacteria with completely sequenced genomes (Galperin et al., 2001; Ashby, 2004; 2006; Galperin, 2004; 2005; 2006; Ulrich and Zhulin, 2010; Letunic et al., 2015; Ortet et al., 2015; Finn et al., 2016) and used these data to analyze trends in microbial genome evolution (Ulrich et al., 2005; Galperin et al., 2010; Williams and Whitworth, 2010). Since then, the list of experimentally characterized signal transduction systems kept growing. It currently includes those transmitting signals from a dozen or so types of sensory proteins: HKs (two-component systems); methyl-accepting chemotaxis proteins (MCPs); membrane components of the PTS; adenylate cyclases and cAMP phosphodiesterases; diguanylate cyclases and c-di-GMP-specific phosphodiesterases; diadenylate cyclases and c-di-AMP-specific phosphodiesterases; extracytoplasmic function (ECF) sigma factors, and Ser/Thr/Tyr protein kinases and phosphoprotein phosphatases (Table 1). This list is probably incomplete: there are other signaling systems, e.g. those involving ppGpp (Potrykus and Cashel, 2008; Kamarthapu et al., 2016) and cGAMP (Davies et al., 2012; Severin et al., 2018), which appear to be involved primarily in intracellular surveillance but could also be involved in environmental sensing. There is also the most common regulatory mechanism that involves LacI-like transcriptional regulators consisting of a sensory (ligand-binding) and a DNA-binding domain, but these are typically confined to the cytosol.

Table 1.

Distribution of environmental sensors in selected bacteria

Organism, strain name Genome size, kb HK MCP PTS EIIC cAMP c-di-GMP signaling c-di-AMP signaling ECF sigma Ser/Thr/Tyr~P
ACI, ACIII CPD GGDEF GGDEF +EAL EAL HD-GYP DisA_N GbpP PgpH STYK PP2C
Escherichia coli K-12 4,639 30 5 23 1 1 12 7 10 – – – – 2 5 1
Bacillus subtilis 168 4,216 36 10 16 – – 3 1 2 – 3 1 1 7 4 5
Mycobacterium tuberculosis H37Rv 4,412 14 – – 16 1 – 1 1 – 1 1 – 10 13 2
Porphyromonas gingivalis W83 2,343 6 – – – – – – – – 1 1 1 6 – –
Neisseria gonorrhoeae FA 1090 2,154 4 – – – – – – – – – – – 1 1 –
Streptococcus pyogenes M1 GAS 1,852 12 – 14 – – – – – 1 2 – 2 1 1
Haemophilus influenzae Rd KW20 1,830 4 – 1 1 1 – – – – – – – 2 1 –
Helicobacter pylori 26695 1,668 4 4 – – – – – – – – – – – 1 1
Treponema pallidum str. Nichols 1,138 1 4 – 1 – 1 – – 3 1 1 1 1 1 3
Rickettsia typhi str. Wilmington 1,111 4 – – – – 1 – 1 – – – – – 1 –
Chlamydia trachomatis D/UW-3/Cx 1,043 1 – – – 1 – – – – 1 – – – 3 3
Mycoplasma pneumoniae M129 816 – – 4 – – – – – – 1 2 – 1 1 1
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Abbreviations are as defined in the text. The numbers are from the COG database (Galperin et al., 2015), where available, or from the results of iterative PSI-BLAST searches of domain-specific profiles against the protein sets encoded in each organism (see Galperin, 2005, for details). A hyperlinked version of this table is available in the Supplementary Materials; an earlier version is on the NCBI web site: https://www.ncbi.nlm.nih.gov/Complete_Genomes/SignalCensus.html.

Each of these sensor types involves a specific kind of signal transduction machinery:

  • Two-component systems involve sensor HKs, which respond to the environmental or intracellular cues by autophosphorylation, followed by the phosphoryl group transfer to the REC domain in their cognate RRs. Depending on the nature of the output domains (if present), RRs may serve as transcriptional regulators, control flagellar or twitching motility, or control other signaling systems, for example, by synthesizing or hydrolyzing second messengers cAMP or c-di-GMP (Galperin, 2006; 2010; Gao et al., 2007; Gao and Stock, 2009; Zschiedrich et al., 2016).

  • Methyl-accepting chemotaxis sensor proteins (MCPs) respond to their respective signals by interacting with the chemotaxis-specific HK CheA, which causes phosphorylation of the stand-alone REC domain RR CheY. Interaction of CheY~P with the flagellar FliM protein affects the direction of flagellar rotation. (Ortega et al., 2017; Salah Ud-Din and Roujeinikova, 2017; Bi and Sourjik, 2018). Some MCPs serve as inputs for alternative signal transduction pathways (Hickman et al., 2005; Willett and Kirby, 2011). A great majority of MCPs have extracytoplasmic sensor domains, but some MCPs are intracellular.

  • Membrane components of the PTS, EIIC proteins (or domains), serve as receptors for a variety of mono- and oligosaccharides. In the absence of their sugar substrates, soluble PTS components are maintained in the phosphorylated state by a complex phosphorylation cascade that typically includes phosphoenolpyruvate, common PTS proteins EI and HPr, and the sugar-specific proteins (or domains) EIIA and EIIB. Sugar binding to EIIC’s leads to the phosphoryl transfer from the respective EIIB~P to this sugar, which causes temporary dephosphorylation of the proteins in that specific cascade. Non-phosphorylated PTS components can bind to a variety of target proteins, such as the gammaproteobacterial (class I) adenylate cyclase, certain membrane permeases and transcriptional regulators, typically inhibiting their activity. In addition, some of them may serve as chemotactic signals (Deutscher et al., 2006; 2014; Deutscher, 2008; Västermark and Saier, 2014).

  • Adenylate cyclases, enzymes that produce second messenger 3’,5’-cyclic adenosine monophosphate (cAMP) are found in several distinct classes, at least two of which are involved in bacterial signal transduction. Class I enzymes (ACI), found in gammaproteobacteria and several deltaproteobacteria, are regulated by the PTS EIIAGlc and possibly other EIIA’s. Class III enzymes (ACIII), found in most bacterial phyla, usually contain N-terminal sensor domain and are regulated by the respective environmental and/or intracellular cues. cAMP-mediated signal transduction involves interaction of the cAMP with specific binding domains, found in the transcriptional regulator CRP and in several other proteins. The cAMP-CRP complex serves as a global regulator that binds to the chromosomal DNA and activates transcription from a variety of bacterial promotors. In P. aeruginosa, a class III adenylate cyclase with membrane-embedded MASE2 sensor domain (PA3217) proved to be a key regulator of virulence (Smith et al., 2004). Flooding the host cell with cAMP, which inhibits phagocytosis and causes cytolysis and apoptosis of macrophages, may be a common mechanism of pathogenesis involving both sensory (class I, class III) and secreted toxin (class II) adenylate cyclases. Ligands for most receptor adenylate cyclases have not yet been identified (Bassler et al., 2018).

  • cAMP-hydrolyzing phosphodiesterases (CPDs) usually represent stand-alone proteins without any sensor domains. Their regulation by environmental or intracellular cues has not yet been demonstrated, but a recent paper described involvement of CpdA in regulation of persistence state in E. coli (Nosho et al., 2018).

  • Diguanylate cyclases (DGCs, proteins with the conserved GGDEF domains) respond to environmental or intracellular signals by synthesizing the second messenger 3’,5’-cyclic dimeric guanosine monophosphate (c-di-GMP). Cyclic di-GMP has been shown to regulate a variety of systems, including motility, protein and polysaccharide secretion, cell division, and biofilm formation. In bacterial pathogens, c-di-GMP is often involved in regulating the expression of virulence factors (Cotter and Stibitz, 2007; Hengge, 2009; Römling et al., 2013; Jenal et al., 2017). Effects of c-di-GMP are mediated by its binding to a variety of receptors that include PilZ and MshEN domains, several types of transcriptional regulators, diguanylate cyclases themselves and other binding proteins (Chou and Galperin, 2016; Krasteva and Sondermann, 2017).

  • C-di-GMP-specific phosphodiesterases (PDEs, containing either EAL or HD-GYP domains) hydrolyze c-di-GMP to linear pGpG to reverse the effects of the DGCs and affect a variety of c-di-GMP-regulated systems. Many PDEs have extracytoplasmic or intracellular sensor domains, which allow them to regulate c-di-GMP levels independently of the respective DGCs. Escherichia coli, for one, encodes five different PDEs with closely related CSS sensor domains that apparently monitor the redox status in the periplasm (Herbst et al., 2018). Some inactivated EAL and HD-GYP domains function as c-di-GMP-binding proteins (Chou and Galperin, 2016; Jenal et al., 2017).

  • Diadenylate cyclases (DACs, containing the conserved the DisA_N domain) produce second messenger 3’,5’-cyclic dimeric adenosine monophosphate (c-di-AMP). Cyclic di-AMP has been shown to mediate signaling related to K+ ion transport, osmotic pressure inside the cell, and cell wall stress (Corrigan and Gründling, 2013; Gründling and Lee, 2016; Commichau et al., 2015; 2018). In B. subtilis, one of its three DACs monitors the integrity of chromosomal DNA and serves as a checkpoint for the cells entering the sporulation process.

  • C-di-AMP-specific phosphodiesterases (CDAs, containing either GGDEF-DHHA-DHHA1 or HD-type domains) hydrolyze c-di-AMP. Most, albeit not all of them do not contain any sensor domains and apparently simply reverse the effects of DACs.

  • Extracytoplasmic function (ECF) sigma factors comprise a vast signal transduction machinery that regulates transcription primarily in response to intracellular cues but can also respond to environmental factors, such as envelope stress (Helmann, 2016; Asai, 2018), blue light (Gaidenko et al., 2006), or extracellular polysaccharides (Kahel-Raifer et al., 2010; Yaniv et al., 2014), see (Mascher, 2013; Paget, 2015; Sineva et al., 2017) for reviews.

  • Signal transduction from Ser/Thr/Tyr protein kinases (STYKs) involves direct or indirect phosphorylation of various (mostly unknown) targets. The few experimentally characterized targets of Ser/Thr/Tyr protein phosphorylation include metabolic (e.g. glycolytic) enzymes and transcriptional regulators. However, Ser/Thr/Tyr phosphorylation affects hundreds of diverse proteins (Macek et al., 2007; 2008) and the full scope of its effects on the cell behavior remains obscure (Kennelly, 2002; Grangeasse et al., 2012; Hansen et al., 2013; Wright and Ulijasz, 2014).

  • Ser/Thr/Tyr phosphoprotein phosphatases (PP2Cs) dephosphorylate Ser, Thr, and/or Tyr residues, both in STYK protein kinases and in their targets and reverse the effects of Ser/Thr/Tyr phosphorylation (Wright and Ulijasz, 2014).

A tally of these types of proteins in two model organisms, E. coli and B. subtilis, and in several widespread pathogens is presented in Table 1 with detail listings provided in Supplementary Tables S1–S3. Similar lists for many other organisms are available at https://www.ncbi.nlm.nih.gov/Complete_Genomes/SignalCensus.html as well as at several other web sites (Ulrich and Zhulin, 2010; Ortet et al., 2015).

This analysis showed that the range of compounds sensed by E. coli provides a reasonable coverage of the entire metabolic map (Galperin, 2009a; 2009b). Indeed, although each sensory system displays certain bias (the PTS only senses sugars, MCPs sense only a small number of compounds), taken in its totality, the signal transduction machinery of E. coli pretty much covers the key physicochemical parameters (to, pH, oxygen levels) and nutrients (amino acids, peptides, mono- and disaccharides, nucleobases) that this bacterium encounters in its environment. In B. subtilis, many receptors still remain uncharacterized (Table S2) but the list of sensed compounds again appears to cover most, if not all, bases. A remarkable number of HKs, DGCs, PDEs, and DACc in both organisms are sensing general parameters of cellular well-being, such as envelope and osmotic stress, the redox state of the cell, and the availability of terminal electron acceptors. Obviously, these parameters greatly influence the lifestyle choices (growth vs. persistence, motility vs. sessility, planktonic vs. biofilm state) in both E. coli and B. subtilis.

Table 1 shows that bacterial pathogens typically encode fewer environmental sensors and have a biased distribution of those that they do encode. Mycobacterium tuberculosis, whose genome is similar in size to those of E. coli and B. subtilis, does not have any chemotaxis or PTS sensors, codes for fewer HKs and c-di-GMP turnover proteins, but has dramatically expanded sets of adenylate cyclases and Ser/Thr/Tyr kinases. Streptococcus pyogenes encodes 12 HKs and 14 EIIC components of the PTS but few, if any, other receptors.

Table S3 presents the lists of sensory proteins encoded in the genomes of ten widespread bacterial pathogens ranging in size from 816 kb in Mycoplasma pneumoniae to 4,412 kb in M. tuberculosis. Each such sensor protein is characterized with respect to (i) which signal (ligand) it is sensing, and (ii) which genes and/or systems it regulates; there are also hyperlinks to the respective entries in UniProt and PubMed (The UniProt Consortium, 2017). This listing clearly shows that, although signal transduction pathways in pathogenic bacteria are streamlined compared to those in free-living E. coli and B. subtilis (not to mention the highly sophisticated signaling machineries of P. aeruginosa or V. cholerae), only few of them have been studied in sufficient detail. There is not a single organism for which all sensed signals have been characterized and all genes or pathways regulated by these signals have been identified. Haemophilus influenzae and Mycoplasma pneumoniae, the first bacteria with completely sequenced genomes, fare somewhat better than the others, owing to the long history of research and relatively small sets of sensor molecules.

The importance of tuberculosis as health hazard in many countries and the relative resilience of M. tuberculosis to most standard treatments made this organism the subject of several research projects aimed at better understanding its signaling systems and their roles in virulence (Shenoy et al., 2004; Bretl et al., 2011; Parish, 2014; Prisic and Husson, 2014). It is also one of very few bacteria for which the researchers were prepared to get away from wide-spectrum antibiotics and consider organism-specific treatments and drugs. Indeed, several HKs (Parish et al., 2003; Rybniker et al., 2014), adenylate cyclases (Agarwal et al., 2009; Shleeva et al., 2017), and Ser/Thr/Tyr protein kinases and phosphatases (Wong et al., 2013; Sherman and Grundner, 2014) have been experimentally characterized and shown to contribute to virulence. As a result, targeting these systems has been proposed as a viable method of controlling M. tuberculosis infection (Bai et al., 2011; Prisic and Husson, 2014; Dey et al., 2015).

The chemotaxis machinery of Helicobacter pylori has been comprehensively studied due to the early recognition that H. pylori relies on chemotaxis for colonization of gastric mucosa (Foynes et al., 2000; Andermann et al., 2002), which leads to the stomach infection and inflammation of the gastric epithelial tissue (Croxen et al., 2006; Williams et al., 2007; Rolig et al., 2012; Huang et al., 2015). Although all four MCPs (TlpA-TlpD) of H. pylori have been experimentally characterized (see Table S3), this bacterium exhibits chemotactic responses to various amino acids and bile acids, which have not yet been assigned to any of these chemoreceptors (Machuca et al., 2017). There is also some understanding of the functions of the H. pylori’s HKs (Waidner et al., 2005; Joseph and Beier, 2007; Marcus et al., 2012; Tsang et al., 2015) but not of its Ser/Thr/Tyr protein kinase and phosphatase.

For most other organisms, understanding of signaling mechanisms is very limited (Table S3). We do not know which environmental parameters these organisms sense, let alone why they choose these parameters and not others. The cases of Chlamydia trachomatis, the causative agent of trachoma, venereal lymphogranuloma and other diseases, and Treponema pallidum, the causative agent of syphilis, are particularly frustrating. The first of them encodes just a single HK, three Ser/Thr/Tyr kinases and three phosphoprotein phosphatases. The second one encodes just four chemoreceptors and a single chemotactic HK, CheA, single copies of an adenylate cyclase, diadenylate cyclase and diguanylate cyclase, and several phosphodiesterases (Table S3). Chlamydia is an obligate intracellular pathogen, while T. pallidum only grows properly in animal tissues, so investigating their signaling capacities in vivo is very challenging. Further, bioinformatics studies, including now-popular “Big Data” approaches, are of limited value: an alignment of Chlamydia-specific sensor domains of Ser/Thr/Tyr kinases and phosphatases would not help when none of the respective proteins has been experimentally characterized. Even when these sensor domains belong to known protein families (e.g. GAF, dCache, 7TMR_HDED, as is the case with several T. pallidum proteins), these assignments are not specific enough to pinpoint the exact ligand. This means that identification of these signals (ligands) will have to be done experimentally, by cloning and heterogenous expression of sensor domains from these organisms. The fact that this has rarely been undertaken for any common pathogens demonstrates the prevailing attitude towards bacterial signaling systems as something only marginally relevant to pathogenesis.

Despite this general attitude, there has been certain progress in harnessing bacterial signaling systems to elicit favorable responses. The natural inclination is to search for compounds (waldiomycin, 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, managing – or even preventing – disease does not necessarily require eradication of the bacteria. For example, an HK inhibitor walkmycin C showed the ability to suppress biofilm formation at sub-MIC levels, without killing the bacteria (Eguchi et al., 2011). There is a long list of potential HK inhibitors (Bem et al., 2015); it might make sense to examine them for the ability to decrease virulence at sub-MIC levels. Biofilm formation could also be repressed by modulating c-di-GMP polls with spermine and spermidine (Sobe et al., 2017). Further, relatively low levels of nitric oxide trigger biofilm dispersal in multiple bacteria (Barraud et al., 2009; Cutruzzola and Frankenberg-Dinkel, 2016), apparently also acting through c-di-GMP signaling. Future studies of the bacterial signaling pathways will likely uncover more simple and non-toxic compounds that could be used for taming the infection and preventing secretion of virulence factors.

While ‘fooling’ bacterial pathogens offers a number of advantages over killing them, there is obviously no guarantee that it will always work, not only because we do not have the required depth of knowledge. Single-approach tricks, such as anti-biofilm treatment alone, may not work simply because bacteria readily adapt to changes that do not involve essential processes (and mutate if the affected process is essential). That is why one may have to utilize multi-target approaches, simultaneously ‘tricking’ all bacterial senses,

Summing up, what do bacteria want? Obviously, they like their amino acids, peptides, mono- and disaccharides, nucleobases and vitamins and get stressed when nutrients become scarce. They usually like ambient pH and often perceive membrane-penetrating acids as repellents. They differ in their preferred redox environments but tightly monitor the redox conditions around them and inside the cell. They really care about the integrity of their domicile and possess multiple systems to detect envelope stress. In general, bacteria seem to be able to adjust to a variety of conditions but do not like abrupt changes; this may provoke them to respond by secreting virulence factors. A better understanding of their preferences could go a long way towards allowing a more amicable co-existence with our bacterial neighbors.

Supplementary Material

SupplTables S1-S3

Acknowledgements

I thank Mark Gomelsky, Antoine Danchine, Kim Lewis, Juan Luis Ramos, Ute Römling, Joachim Schultz and Ken Timmis for many helpful comments. This work was supported by the by the Intramural Research Program of the National Institutes of Health at the U.S. National Library of Medicine.

References

  1. Agarwal N, Lamichhane G, Gupta R, Nolan S, and Bishai WR (2009) Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase. Nature 460: 98–102. [DOI] [PubMed] [Google Scholar]
  2. Andermann TM, Chen YT, and Ottemann KM (2002) Two predicted chemoreceptors of Helicobacter pylori promote stomach infection. Infect Immun 70: 5877–5881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Asai K (2018) Anti-sigma factor-mediated cell surface stress responses in Bacillus subtilis. Genes Genet Syst 92: 223–234. [DOI] [PubMed] [Google Scholar]
  4. Ashby MK (2004) Survey of the number of two-component response regulator genes in the complete and annotated genome sequences of prokaryotes. FEMS Microbiol Lett 231: 277–281. [DOI] [PubMed] [Google Scholar]
  5. Ashby MK (2006) Distribution, structure and diversity of “bacterial” genes encoding two-component proteins in the Euryarchaeota. Archaea 2: 11–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bai G, Knapp GS, and McDonough KA (2011) Cyclic AMP signalling in mycobacteria: redirecting the conversation with a common currency. Cell Microbiol 13: 349–358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Barraud N, Storey MV, Moore ZP, Webb JS, Rice SA, and Kjelleberg S (2009) Nitric oxide-mediated dispersal in single- and multi-species biofilms of clinically and industrially relevant microorganisms. Microb Biotechnol 2: 370–378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bassler J, Schultz JE, and Lupas AN (2018) Adenylate cyclases: receivers, transducers, and generators of signals. Cell Signal 46: 135–144. [DOI] [PubMed] [Google Scholar]
  9. Bell G, and MacLean C (2018) The search for ‘evolution-proof’ antibiotics. Trends Microbiol 26: 471–483. [DOI] [PubMed] [Google Scholar]
  10. Bem AE, Velikova N, Pellicer MT, Baarlen P, Marina A, and Wells JM (2015) Bacterial histidine kinases as novel antibacterial drug targets. ACS Chem Biol 10: 213–224. [DOI] [PubMed] [Google Scholar]
  11. Bi S, and Sourjik V (2018) Stimulus sensing and signal processing in bacterial chemotaxis. Curr Opin Microbiol 45: 22–29. [DOI] [PubMed] [Google Scholar]
  12. Bretl DJ, Demetriadou C, and Zahrt TC (2011) Adaptation to environmental stimuli within the host: two-component signal transduction systems of Mycobacterium tuberculosis. Microbiol Mol Biol Rev 75: 566–582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Buffing MF, Link H, Christodoulou D, and Sauer U (2018) Capacity for instantaneous catabolism of preferred and non-preferred carbon sources in Escherichia coli and Bacillus subtilis. Sci Rep 8: 11760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chou SH, and Galperin MY (2016) Diversity of cyclic di-GMP-binding proteins and mechanisms. J Bacteriol 198: 32–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Commichau FM, Dickmanns A, Gundlach J, Ficner R, and Stülke J (2015) A jack of all trades: the multiple roles of the unique essential second messenger cyclic di-AMP. Mol Microbiol 97: 189–204. [DOI] [PubMed] [Google Scholar]
  16. Commichau FM, Gibhardt J, Halbedel S, Gundlach J, and Stülke J (2018) A delicate connection: c-di-AMP affects cell integrity by controlling osmolyte transport. Trends Microbiol 26: 175–185. [DOI] [PubMed] [Google Scholar]
  17. Corrigan RM, and Gründling A (2013) Cyclic di-AMP: another second messenger enters the fray. Nat Rev Microbiol 11: 513–524. [DOI] [PubMed] [Google Scholar]
  18. Cotter PA, and Stibitz S (2007) c-di-GMP-mediated regulation of virulence and biofilm formation. Curr Opin Microbiol 10: 17–23. [DOI] [PubMed] [Google Scholar]
  19. Croxen MA, Sisson G, Melano R, and Hoffman PS (2006) The Helicobacter pylori chemotaxis receptor TlpB (HP0103) is required for pH taxis and for colonization of the gastric mucosa. J Bacteriol 188: 2656–2665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Cutruzzola F, and Frankenberg-Dinkel N (2016) Origin and impact of nitric oxide in Pseudomonas aeruginosa biofilms. J Bacteriol 198: 55–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Davies BW, Bogard RW, Young TS, and Mekalanos JJ (2012) Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence. Cell 149: 358–370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Deutscher J (2008) The mechanisms of carbon catabolite repression in bacteria. Curr Opin Microbiol 11: 87–93. [DOI] [PubMed] [Google Scholar]
  23. Deutscher J, Francke C, and Postma PW (2006) How phosphotransferase system-related protein phosphorylation regulates carbohydrate metabolism in bacteria. Microbiol Mol Biol Rev 70: 939–1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Deutscher J, Ake FM, Derkaoui M, Zebre AC, Cao TN, Bouraoui H, et al. (2014) The bacterial phosphoenolpyruvate:carbohydrate phosphotransferase system: regulation by protein phosphorylation and phosphorylation-dependent protein-protein interactions. Microbiol Mol Biol Rev 78: 231–256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Dey B, Dey RJ, Cheung LS, Pokkali S, Guo H, Lee JH, and Bishai WR (2015) A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis. Nat Med 21: 401–406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Eguchi Y, Kubo N, Matsunaga H, Igarashi M, and Utsumi R (2011) Development of an antivirulence drug against Streptococcus mutans: repression of biofilm formation, acid tolerance, and competence by a histidine kinase inhibitor, walkmycin C. Antimicrob Agents Chemother 55: 1475–1484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Fabret C, Feher VA, and Hoch JA (1999) Two-component signal transduction in Bacillus subtilis: how one organism sees its world. J Bacteriol 181: 1975–1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Fakhruzzaman M, Inukai Y, Yanagida Y, Kino H, Igarashi M, Eguchi Y, and Utsumi R (2015) Study on in vivo effects of bacterial histidine kinase inhibitor, Waldiomycin, in Bacillus subtilis and Staphylococcus aureus. J Gen Appl Microbiol 61: 177–184. [DOI] [PubMed] [Google Scholar]
  29. Finn RD, Coggill P, Eberhardt RY, Eddy SR, Mistry J, Mitchell AL, et al. (2016) The Pfam protein families database: towards a more sustainable future. Nucleic Acids Res 44: D279–D285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Foynes S, Dorrell N, Ward SJ, Stabler RA, McColm AA, Rycroft AN, and Wren BW (2000) Helicobacter pylori possesses two CheY response regulators and a histidine kinase sensor, CheA, which are essential for chemotaxis and colonization of the gastric mucosa. Infect Immun 68: 2016–2023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Gaidenko TA, Kim TJ, Weigel AL, Brody MS, and Price CW (2006) The blue-light receptor YtvA acts in the environmental stress signaling pathway of Bacillus subtilis. J Bacteriol 188: 6387–6395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Galperin MY, and Koonin EV (1999) Searching for drug targets in microbial genomes. Curr Opin Biotechnol 10: 571–578. [DOI] [PubMed] [Google Scholar]
  33. Galperin MY, Natale DA, Aravind L, and Koonin EV (1999) A specialized version of the HD hydrolase domain implicated in signal transduction. J Mol Microbiol Biotechnol 1: 303–305. [PMC free article] [PubMed] [Google Scholar]
  34. Galperin MY, Nikolskaya AN, and Koonin EV (2001) Novel domains of the prokaryotic two-component signal transduction systems. FEMS Microbiol Lett 203: 11–21. [DOI] [PubMed] [Google Scholar]
  35. Galperin MY (2004) Bacterial signal transduction network in a genomic perspective. Environ Microbiol 6: 552–567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Galperin MY (2005) A census of membrane-bound and intracellular signal transduction proteins in bacteria: bacterial IQ, extroverts and introverts. BMC Microbiol 5: 35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Galperin MY (2006) Structural classification of bacterial response regulators: diversity of output domains and domain combinations. J Bacteriol 188: 4169–4182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Galperin MY (2009a) Sensory transduction network of E. coli In Systems Biology and Biotechnology of Escherichia coli. Lee SY (ed). Dordrecht: Springer Netherlands, pp. 133–148. [Google Scholar]
  39. Galperin MY (2009b) Sensory transduction in bacteria In Encyclopedia of Microbiology (Third Edition) Schaechter M (ed). pp. 447–463. [Google Scholar]
  40. Galperin MY (2010) Diversity of structure and function of response regulator output domains. Curr Opin Microbiol 13: 150–159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Galperin MY, Higdon R, and Kolker E (2010) Interplay of heritage and habitat in the distribution of bacterial signal transduction systems. Mol Biosyst 6: 721–728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Galperin MY, Makarova KS, Wolf YI, and Koonin EV (2015) Expanded microbial genome coverage and improved protein family annotation in the COG database. Nucleic Acids Res 43: D261–D269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Gao R, Mack TR, and Stock AM (2007) Bacterial response regulators: versatile regulatory strategies from common domains. Trends Biochem Sci 32: 225–234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Gao R, and Stock AM (2009) Biological insights from structures of two-component proteins. Annu Rev Microbiol 63: 133–154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Grangeasse C, Nessler S, and Mijakovic I (2012) Bacterial tyrosine kinases: evolution, biological function and structural insights. Philos Trans R Soc Lond B Biol Sci 367: 2640–2655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Gründling A, and Lee VT (2016) Old concepts, new molecules and current approaches applied to the bacterial nucleotide signalling field. Philos Trans R Soc Lond B Biol Sci 371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Hansen AM, Chaerkady R, Sharma J, Diaz-Mejia JJ, Tyagi N, Renuse S, et al. (2013) The Escherichia coli phosphotyrosine proteome relates to core pathways and virulence. PLoS Pathog 9: e1003403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Hazelbauer GL (2012) Bacterial chemotaxis: the early years of molecular studies. Annu Rev Microbiol 66: 285–303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Helmann JD (2016) Bacillus subtilis extracytoplasmic function (ECF) sigma factors and defense of the cell envelope. Curr Opin Microbiol 30: 122–132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Hengge R (2009) Principles of c-di-GMP signalling in bacteria. Nat Rev Microbiol 7: 263–273. [DOI] [PubMed] [Google Scholar]
  51. Herbst S, Lorkowski M, Sarenko O, Nguyen TKL, Jaenicke T, and Hengge R (2018) Transmembrane redox control and proteolysis of PdeC, a novel type of c-di-GMP phosphodiesterase. EMBO J 37: e97825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Hickman JW, Tifrea DF, and Harwood CS (2005) A chemosensory system that regulates biofilm formation through modulation of cyclic diguanylate levels. Proc Natl Acad Sci USA 102: 14422–14427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Huang JY, Sweeney EG, Sigal M, Zhang HC, Remington SJ, Cantrell MA, et al. (2015) Chemodetection and destruction of host urea allows Helicobacter pylori to locate the epithelium. Cell Host Microbe 18: 147–156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Jenal U, Reinders A, and Lori C (2017) Cyclic di-GMP: second messenger extraordinaire. Nat Rev Microbiol 15: 271–284. [DOI] [PubMed] [Google Scholar]
  55. Joseph B, and Beier D (2007) Global analysis of two-component gene regulation in H. pylori by mutation analysis and transcriptional profiling. Methods Enzymol 423: 514–530. [DOI] [PubMed] [Google Scholar]
  56. Kahel-Raifer H, Jindou S, Bahari L, Nataf Y, Shoham Y, Bayer EA, et al. (2010) The unique set of putative membrane-associated anti-sigma factors in Clostridium thermocellum suggests a novel extracellular carbohydrate-sensing mechanism involved in gene regulation. FEMS Microbiol Lett 308: 84–93. [DOI] [PubMed] [Google Scholar]
  57. Kamarthapu V, Epshtein V, Benjamin B, Proshkin S, Mironov A, Cashel M, and Nudler E (2016) ppGpp couples transcription to DNA repair in E. coli. Science 352: 993–996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Kennelly PJ (2002) Protein kinases and protein phosphatases in prokaryotes: a genomic perspective. FEMS Microbiol Lett 206: 1–8. [DOI] [PubMed] [Google Scholar]
  59. Krasteva PV, and Sondermann H (2017) Versatile modes of cellular regulation via cyclic dinucleotides. Nat Chem Biol 13: 350–359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Letunic I, Doerks T, and Bork P (2015) SMART: recent updates, new developments and status in 2015. Nucleic Acids Res 43: D257–260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, et al. (2015) A new antibiotic kills pathogens without detectable resistance. Nature 517: 455–459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Macek B, Mijakovic I, Olsen JV, Gnad F, Kumar C, Jensen PR, and Mann M (2007) The serine/threonine/tyrosine phosphoproteome of the model bacterium Bacillus subtilis. Mol Cell Proteomics 6: 697–707. [DOI] [PubMed] [Google Scholar]
  63. Macek B, Gnad F, Soufi B, Kumar C, Olsen JV, Mijakovic I, and Mann M (2008) Phosphoproteome analysis of E. coli reveals evolutionary conservation of bacterial Ser/Thr/Tyr phosphorylation. Mol Cell Proteomics 7: 299–307. [DOI] [PubMed] [Google Scholar]
  64. Machuca MA, Johnson KS, Liu YC, Steer DL, Ottemann KM, and Roujeinikova A (2017) Helicobacter pylori chemoreceptor TlpC mediates chemotaxis to lactate. Sci Rep 7: 14089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Marcus EA, Sachs G, Wen Y, Feng J, and Scott DR (2012) Role of the Helicobacter pylori sensor kinase ArsS in protein trafficking and acid acclimation. J Bacteriol 194: 5545–5551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Mascher T (2013) Signaling diversity and evolution of extracytoplasmic function (ECF) sigma factors. Curr Opin Microbiol 16: 148–155. [DOI] [PubMed] [Google Scholar]
  67. Monod J (1942) Recherches sur la croissance des cultures bactériennes Thesis. Paris: Hermann and Cie. [Google Scholar]
  68. Nosho K, Fukushima H, Asai T, Nishio M, Takamaru R, Kobayashi-Kirschvink KJ, et al. (2018) cAMP-CRP acts as a key regulator for the viable but non-culturable state in Escherichia coli. Microbiology 164: 410–419. [DOI] [PubMed] [Google Scholar]
  69. Ortega A, Zhulin IB, and Krell T (2017) Sensory repertoire of bacterial chemoreceptors. Microbiol Mol Biol Rev 81: e00033–00017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Ortet P, Whitworth DE, Santaella C, Achouak W, and Barakat M (2015) P2CS: updates of the prokaryotic two-component systems database. Nucleic Acids Res 43: D536–D541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Paget MS (2015) Bacterial sigma factors and anti-sigma factors: structure, function and distribution. Biomolecules 5: 1245–1265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Parish T, Smith DA, Kendall S, Casali N, Bancroft GJ, and Stoker NG (2003) Deletion of two-component regulatory systems increases the virulence of Mycobacterium tuberculosis. Infect Immun 71: 1134–1140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Parish T (2014) Two-component regulatory systems of mycobacteria. Microbiol Spectr 2: MGM2-0010-2013. [DOI] [PubMed] [Google Scholar]
  74. Potrykus K, and Cashel M (2008) (p)ppGpp: still magical? Annu Rev Microbiol 62: 35–51. [DOI] [PubMed] [Google Scholar]
  75. Prisic S, and Husson RN (2014) Mycobacterium tuberculosis serine/threonine protein kinases. Microbiol Spectr 2: MGM2-0006-2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Rappuoli R, Bloom DE, and Black S (2017) Deploy vaccines to fight superbugs. Nature 552: 165–167. [DOI] [PubMed] [Google Scholar]
  77. Reizer J, Bachem S, Reizer A, Arnaud M, Saier MH Jr., and Stülke J (1999) Novel phosphotransferase system genes revealed by genome analysis - the complete complement of PTS proteins encoded within the genome of Bacillus subtilis. Microbiology 145: 3419–3429. [DOI] [PubMed] [Google Scholar]
  78. Rolig AS, Shanks J, Carter JE, and Ottemann KM (2012) Helicobacter pylori requires TlpD-driven chemotaxis to proliferate in the antrum. Infect Immun 80: 3713–3720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Römling U, Galperin MY, and Gomelsky M (2013) Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev 77: 1–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Rybniker J, Chen JM, Sala C, Hartkoorn RC, Vocat A, Benjak A, et al. (2014) Anticytolytic screen identifies inhibitors of mycobacterial virulence protein secretion. Cell Host Microbe 16: 538–548. [DOI] [PubMed] [Google Scholar]
  81. Salah Ud-Din AIM, and Roujeinikova A (2017) Methyl-accepting chemotaxis proteins: a core sensing element in prokaryotes and archaea. Cell Mol Life Sci 74: 3293–3303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Severin GB, Ramliden MS, Hawver LA, Wang K, Pell ME, Kieninger AK, et al. (2018) Direct activation of a phospholipase by cyclic GMP-AMP in El Tor Vibrio cholerae. Proc Natl Acad Sci USA 115: E6048–E6055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Shenoy AR, Sivakumar K, Krupa A, Srinivasan N, and Visweswariah SS (2004) A survey of nucleotide cyclases in actinobacteria: unique domain organization and expansion of the class III cyclase family in Mycobacterium tuberculosis. Comp Funct Genomics 5: 17–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Sherman DR, and Grundner C (2014) Agents of change - concepts in Mycobacterium tuberculosis Ser/Thr/Tyr phosphosignalling. Mol Microbiol 94: 231–241. [DOI] [PubMed] [Google Scholar]
  85. Shleeva MO, Kondratieva TK, Demina GR, Rubakova EI, Goncharenko AV, Apt AS, and Kaprelyants AS (2017) Overexpression of adenylyl cyclase encoded by the Mycobacterium tuberculosis Rv2212 gene confers improved fitness, accelerated recovery from dormancy and enhanced virulence in mice. Front Cell Infect Microbiol 7: 370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Sineva E, Savkina M, and Ades SE (2017) Themes and variations in gene regulation by extracytoplasmic function (ECF) sigma factors. Curr Opin Microbiol 36: 128–137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Smith RS, Wolfgang MC, and Lory S (2004) An adenylate cyclase-controlled signaling network regulates Pseudomonas aeruginosa virulence in a mouse model of acute pneumonia. Infect Immun 72: 1677–1684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Sobe RC, Bond WG, Wotanis CK, Zayner JP, Burriss MA, Fernandez N, et al. (2017) Spermine inhibits Vibrio cholerae biofilm formation through the NspS-MbaA polyamine signaling system. J Biol Chem 292: 17025–17036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Szurmant H, and Ordal GW (2004) Diversity in chemotaxis mechanisms among the bacteria and archaea. Microbiol Mol Biol Rev 68: 301–319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. The UniProt Consortium (2017) UniProt: the universal protein knowledgebase. Nucleic Acids Res 45: D158–D169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Tsang J, Hirano T, Hoover TR, and McMurry JL (2015) Helicobacter pylori FlhA binds the sensor kinase and flagellar gene regulatory protein FlgS with high affinity. J Bacteriol 197: 1886–1892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Ulrich LE, Koonin EV, and Zhulin IB (2005) One-component systems dominate signal transduction in prokaryotes. Trends Microbiol 13: 52–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Ulrich LE, and Zhulin IB (2010) The MiST2 database: a comprehensive genomics resource on microbial signal transduction. Nucleic Acids Res 38: D401–D407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Västermark A, and Saier MH Jr. (2014) The involvement of transport proteins in transcriptional and metabolic regulation. Curr Opin Microbiol 18: 8–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Waidner B, Melchers K, Stahler FN, Kist M, and Bereswill S (2005) The Helicobacter pylori CrdRS two-component regulation system (HP1364/HP1365) is required for copper-mediated induction of the copper resistance determinant CrdA. J Bacteriol 187: 4683–4688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Wang R, van Dorp L, Shaw LP, Bradley P, Wang Q, Wang X, et al. (2018) The global distribution and spread of the mobilized colistin resistance gene mcr-1. Nat Commun 9: 1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Watanabe T, Igarashi M, Okajima T, Ishii E, Kino H, Hatano M, et al. (2012) Isolation and characterization of signermycin B, an antibiotic that targets the dimerization domain of histidine kinase WalK. Antimicrob Agents Chemother 56: 3657–3663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Willett JW, and Kirby JR (2011) CrdS and CrdA comprise a two-component system that is cooperatively regulated by the Che3 chemosensory system in Myxococcus xanthus. mBio 2: e00110–00111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Williams RH, and Whitworth DE (2010) The genetic organisation of prokaryotic two-component system signalling pathways. BMC Genomics 11: 720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Williams SM, Chen YT, Andermann TM, Carter JE, McGee DJ, and Ottemann KM (2007) Helicobacter pylori chemotaxis modulates inflammation and bacterium-gastric epithelium interactions in infected mice. Infect Immun 75: 3747–3757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Wong D, Chao JD, and Av-Gay Y (2013) Mycobacterium tuberculosis-secreted phosphatases: from pathogenesis to targets for TB drug development. Trends Microbiol 21: 100–109. [DOI] [PubMed] [Google Scholar]
  102. Wright DP, and Ulijasz AT (2014) Regulation of transcription by eukaryotic-like serine-threonine kinases and phosphatases in Gram-positive bacterial pathogens. Virulence 5: 863–885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Yaniv O, Fichman G, Borovok I, Shoham Y, Bayer EA, Lamed R, et al. (2014) Fine-structural variance of family 3 carbohydrate-binding modules as extracellular biomass-sensing components of Clostridium thermocellum anti-sigmaI factors. Acta Crystallogr D Biol Crystallogr 70: 522–534. [DOI] [PubMed] [Google Scholar]
  104. Zschiedrich CP, Keidel V, and Szurmant H (2016) Molecular mechanisms of two-component signal transduction. J Mol Biol 428: 3752–3775. [DOI] [PMC free article] [PubMed] [Google Scholar]

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