title: A genomic analysis of two-component signal transduction in Streptococcus pneumoniae.
abstract: A genomics-based approach was used to identify the entire gene complement of putative two-component signal transduction systems (TCSTSs) in Streptococcus pneumoniae. A total of 14 open reading frames (ORFs) were identified as putative response regulators, 13 of which were adjacent to genes encoding probable histidine kinases. Both the histidine kinase and response regulator proteins were categorized into subfamilies on the basis of phylogeny. Through a systematic programme of mutagenesis, the importance of each novel TCSTS was determined with respect to viability and pathogenicity. One TCSTS was identified that was essential for the growth of S. pneumoniaeThis locus was highly homologous to the yycFG gene pair encoding the essential response regulator/histidine kinase proteins identified in Bacillus subtilis and Staphylococcus aureus. Separate deletions of eight other loci led in each case to a dramatic attenuation of growth in a mouse respiratory tract infection model, suggesting that these signal transduction systems are important for the in vivo adaptation and pathogenesis of S. pneumoniae. The identification of conserved TCSTSs important for both pathogenicity and viability in a Gram-positive pathogen highlights the potential of two-component signal transduction as a multicomponent target for antibacterial drug discovery.
authors.affiliation: Anti-infectives Research; Bioinformatics, SmithKline Beecham Pharmaceuticals Research and Development, 1250 S. Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Throup
authors.forename: K K
authors.initials: KK
authors.lastname: Koretke
authors.forename: A P
authors.initials: AP
authors.lastname: Bryant
authors.forename: K A
authors.initials: KA
authors.lastname: Ingraham
authors.forename: A F
authors.initials: AF
authors.lastname: Chalker
authors.forename: Y
authors.initials: Y
authors.lastname: Ge
authors.forename: A
authors.initials: A
authors.lastname: Marra
authors.forename: N G
authors.initials: NG
authors.lastname: Wallis
authors.forename: J R
authors.initials: JR
authors.lastname: Brown
authors.forename: D J
authors.initials: DJ
authors.lastname: Holmes
authors.forename: M
authors.initials: M
authors.lastname: Rosenberg
authors.forename: M K
authors.initials: MK
authors.lastname: Burnham
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D016680:Genome, Bacterial; D006639:Histidine / Q000235:genetics; D000071677:Histidine Kinase; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D016296:Mutagenesis; D010802:Phylogeny; D011008:Pneumococcal Infections / Q000382:microbiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000382:microbiology; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000235:genetics* / Q000378:metabolism* / Q000472:pathogenicity
chemical_list: D001426:Bacterial Proteins; D001224:Aspartic Acid; D006639:Histidine; D008780:Methyltransferases; C035181:rRNA (adenosine-O-2'-)methyltransferase; D011494:Protein Kinases; D000071677:Histidine Kinase