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Bacterial Histidine Kinases as Novel Antibacterial Drug Targets
Bem, A.E. ; Velikova, N.R. ; Pellicer, M.T. ; Baarlen, P. van; Marina, A. ; Wells, J.M. - \ 2015
Acs Chemical Biology 10 (2015)1. - ISSN 1554-8929 - p. 213 - 224.
2-component signal-transduction - structure-based discovery - staphylococcus-aureus - mycobacterium-tuberculosis - escherichia-coli - multidrug-resistance - response regulator - vancomycin resistance - antibiotic-resistance - streptococcus-mutans
Bacterial histidine kinases (HKs) are promising targets for novel antibacterials. Bacterial HKs are part of bacterial two-component systems (TCSs), the main signal transduction pathways in bacteria, regulating various processes including virulence, secretion systems and antibiotic resistance. In this review, we discuss the biological importance of TCSs and bacterial HKs for the discovery of novel antibacterials, as well as published TCS and HK inhibitors that can be used as a starting point for structure-based approaches to develop novel antibacterials.
A transcriptional study of acidogenic chemostat cells of Clostridium acetobutylicum - Cellular behavior in adaptation to n-butanol
Schwarz, K.M. ; Kuit, W. ; Grimmler, C. ; Ehrenreich, A. ; Kengen, S.W.M. - \ 2012
Journal of Biotechnology 161 (2012)3. - ISSN 0168-1656 - p. 366 - 377.
fatty-acid biosynthesis - 2-component signal-transduction - organic-solvent tolerance - response regulator yycf - beijerinckii ncimb 8052 - gram-negative bacteria - escherichia-coli - bacillus-subtilis - lipid-composition - gene-expression
To gain more insight into the butanol stress response of Clostridium acetobutylicum the transcriptional response of a steady state acidogenic culture to different levels of n-butanol (0.25-1%) was investigated. No effect was observed on the fermentation pattern and expression of typical solvent genes (aad, ctfA/B, adc, bdhA/B, ptb, buk). Elevated levels of butanol mainly affected class I heat-shock genes (hrcA, grpE, dnaK, dnaJ, groES, groEL, hsp90), which were upregulated in a dose- and time-dependent manner, and genes encoding proteins involved in the membrane composition (fab and fad or glycerophospholipid related genes) and various ABC-transporters of unknown specificity. Interestingly, fab and fad genes were embedded in a large, entirely repressed cluster (CAC1988-CAC2019), which inter alia encoded an iron-specific ABC-transporter and molybdenum-cofactor synthesis proteins. Of the glycerophospholipid metabolism, the glycerol-3-phosphate dehydrogenase (glpA) gene was highly upregulated, whereas a glycerophosphodiester ABC-transporter (ugpAEBC) and a phosphodiesterase (ugpC) were repressed. On the megaplasmid, only a few genes showed differential expression, e.g. a rare lipoprotein (CAP0058, repressed) and a membrane protein (CAP0102, upregulated) gene. Observed transcriptional responses suggest that C. acetobutylicum reacts to butanol stress by induction of the general stress response and changing its cell envelope and transporter composition, but leaving the central catabolism unaffected
A multicomponent sugar phosphate sensor system specifically induced in Bacillus cereus during infection of the insect gut
Song, F. ; Peng, Q. ; Brillard, J. ; Buisson, C. ; Been, M.W.H.J. de; Abee, T. ; Broussolle, V. ; Huang, D. ; Zhang, J. ; Lereclus, D. ; Nielsen-LeRoux, C. - \ 2012
FASEB Journal 26 (2012)8. - ISSN 0892-6638 - p. 3336 - 3350.
2-component signal-transduction - gram-positive bacteria - plcr virulence regulon - low-gc-content - escherichia-coli - in-vivo - functional-analysis - histidine kinases - genome sequence - gene-expression
Using a previously developed Bacillus cereus in vivo expression technology (IVET) promoter trap system, we showed that spsA, a gene of unknown function, was specifically expressed in the larval gut during infection. Search for gut-related compounds inducing spsA transcription identified glucose-6-phosphate (G6P) as an activation signal. Analysis of the spsA-related 5-gene cluster indicated that SpsA is part of a new sugar phosphate sensor system composed of a 2-component system (TCS) encoded by spsR and spsK, and 2 additional downstream genes, spsB and spsC. In B. cereus, American Type Culture Collection (ATCC) 14579, spsRK, and spsABC are separate transcriptional units, of which only spsABC was activated by extracellular G6P. lacZ transcriptional fusions tested in mutant and complemented strains showed that SpsRK, SpsA, and SpsB are essential for the transcription of spsABC. Deletion mutant analysis showed that SpsC is essential for the G6P uptake. gfp-transcriptional fusions showed that these genes are required for host-activated expression, as well. This sugar phosphate sensor and transport system is found in pathogenic Bacillus group and Clostridia bacteria and may be important for host adaptation. Our findings provide new insights into the function of 2-component sensor systems in host-pathogen interactions, specifically in the gut.—Song, F., Peng, Q., Brillard, J., Buisson, C., de Been, M., Abee, T., Broussolle, V., Huang, D., Zhang, J., Lereclus, D., Nielsen-LeRoux, C. A multicomponent sugar phosphate sensor system specifically induced in Bacillus cereus during infection of the insect gut.
Novel SigB regulation modules of Gram-positive bacteria involve the use of complex hybrid histidine kinases
Been, M.W.H.J. de; Francke, C. ; Siezen, R.J. ; Abee, T. - \ 2011
Microbiology 157 (2011)1. - ISSN 1350-0872 - p. 3 - 12.
general stress-response - 2-component signal-transduction - bacillus-subtilis - streptomyces-coelicolor - transcription factor - energy stress - phosphatase 2c - osmotic-stress - pathway - protein
A common bacterial strategy to cope with stressful conditions is the activation of alternative sigma factors that control specific regulons enabling targeted responses. In the human pathogen Bacillus cereus, activation of the major stress-responsive sigma factor sB is controlled by a signalling route that involves the multi-sensor hybrid histidine kinase RsbK. RsbK-type kinases are not restricted to the B. cereus group, but occur in a wide variety of other bacterial species, including members of the the low-GC Gram-positive genera Geobacillus and Paenibacillus as well as the high-GC actinobacteria. Genome context and protein sequence analyses of 118 RsbK homologues revealed extreme variability in N-terminal sensory as well as C-terminal regulatory domains and suggested that RsbK-type kinases are subject to complex fine-tuning systems, including sensitization and desensitization via methylation and demethylation within the helical domain preceding the H-box. The RsbK-mediated stress-responsive sigma factor activation mechanism that has evolved in B. cereus and the other species differs markedly from the extensively studied and highly conserved RsbRST-mediated sB activation route found in Bacillus subtilis and other low-GC Gram-positive bacteria. Implications for future research on sigma factor control mechanisms are presented and current knowledge gaps are briefly discussed.
A novel hybrid kinase is essential for regulating the sigmaB-mediated stress response of Bacillus cereus
Been, M.W.H.J. de; Tempelaars, M.H. ; Schaik, W. van; Moezelaar, R. ; Siezen, R.J. ; Abee, T. - \ 2010
Environmental Microbiology 12 (2010)3. - ISSN 1462-2912 - p. 730 - 745.
gram-positive bacteria - 2-component signal-transduction - multiple sequence alignment - tumefaciens vira protein - agrobacterium-tumefaciens - gene-expression - energy stress - subtilis - domains - identification
A common bacterial strategy for monitoring environmental challenges is to use two-component systems, which consist of a sensor histidine kinase (HK) and a response regulator (RR). In the food-borne pathogen Bacillus cereus, the alternative sigma factor sB is activated by the RR RsbY. Here we present strong indications that the PP2C-type phosphatase RsbY receives its input from the multi-sensor hybrid kinase BC1008 (renamed RsbK). Genome analyses revealed that, across bacilli, rsbY and rsbK are located in a conserved gene cluster. A B. cereus rsbK deletion strain was shown to be incapable of inducing sB upon stress conditions and was impaired in its heat adaptive response. Comparison of the wild-type and rsbK mutant transcriptomes upon heat shock revealed that RsbK was primarily involved in the activation of the sB-mediated stress response. Truncation of the RsbK RR receiver domain demonstrated the importance of this domain for sB induction upon stress. The domain architecture of RsbK suggests that in the B. cereus group and in other bacilli, environmental and intracellular stress signalling routes are combined into one single protein. This strategy is markedly different from the sB activation pathway in other low-GC Gram-positives.
High-throughput PCR Screening of Genes for Three-component Regulatory System Putatively involved in Quorum Sensing from Low-G+C Gram-positive Bacteria
Nakayama, J. ; Akkermans, A.D.L. ; Vos, W.M. de - \ 2003
Bioscience, Biotechnology and Biochemistry 67 (2003)3. - ISSN 0916-8451 - p. 480 - 489.
biosynthesis-activating pheromone - 2-component signal-transduction - lactobacillus-plantarum c-11 - complete genome sequence - gram-positive bacteria - streptococcus-pneumoniae - enterococcus-faecalis - bacillus-subtilis - staphylococcus-aureus - competence-phero
Quorum sensing of Gram-positive bacteria is often regulated by three-component regulatory system composed of autoinducing peptide, sensor kinase and response regulator. We used PCR to study a gene cassette encoding this three-component regulatory system. Degenerate primers were designed from consensus amino acid sequences in the HPK10 subfamily, mostly involved in quorum sensing. Products amplified from genomic DNA of Lactobacillus, Enterococcus, and Clostridium species were cloned and sequenced; their deduced amino acid sequences were similar to those of members of the HPK10 subfamily. Complete genes for the putative gene cassette were cloned by inverse PCR from L. paracasei E93490 and L. plantarum WCFS6. Phylogenetic analysis grouped the cloned putative HPKs into the HPK10 subfamily. These results indicated the usefulness of this high-throughput gene screening and suggested that the three-component regulatory gene cassette are widely present.