title: Inspecting the potential physiological and biomedical value of 44 conserved uncharacterised proteins of Streptococcus pneumoniae.
abstract: BACKGROUND
  The major Gram-positive coccoid pathogens cause similar invasive diseases and show high rates of antimicrobial resistance. Uncharacterised proteins shared by these organisms may be involved in virulence or be targets for antimicrobial therapy.
  
  
  RESULTS
  Forty four uncharacterised proteins from Streptococcus pneumoniae with homologues in Enterococcus faecalis and/or Staphylococcus aureus were selected for analysis. These proteins showed differences in terms of sequence conservation and number of interacting partners. Twenty eight of these proteins were monodomain proteins and 16 were modular, involving domain combinations and, in many cases, predicted unstructured regions. The genes coding for four of these 44 proteins were essential. Genomic and structural studies showed one of the four essential genes to code for a promising antibacterial target. The strongest impact of gene removal was on monodomain proteins showing high sequence conservation and/or interactions with many other proteins. Eleven out of 40 knockouts (one for each gene) showed growth delay and 10 knockouts presented a chaining phenotype. Five of these chaining mutants showed a lack of putative DNA-binding proteins. This suggest this phenotype results from a loss of overall transcription regulation. Five knockouts showed defective autolysis in response to penicillin and vancomycin, and attenuated virulence in an animal model of sepsis.
  
  
  CONCLUSIONS
  Uncharacterised proteins make up a reservoir of polypeptides of different physiological importance and biomedical potential. A promising antibacterial target was identified. Five of the 44 examined proteins seemed to be virulence factors.
authors.affiliation: Centro Nacional de Microbiología and CIBERES (CIBER de Enfermedades Respiratorias), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. mgaliano@isciii.es.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Martín-Galiano
authors.forename: José
authors.initials: J
authors.lastname: Yuste
authors.forename: María I
authors.initials: MI
authors.lastname: Cercenado
authors.forename: Adela G
authors.initials: AG
authors.lastname: de la Campa
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D035843:Biomedical Research; D017124:Conserved Sequence; D055786:Gene Knockout Techniques; D010641:Phenotype; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins
references.citation: PLoS Biol. 2009 Sep;7(9):e1000205
references.pmid: 19787035
references.citation: Clin Microbiol Infect. 2009 Mar;15(3):212-7
references.pmid: 19335368
references.citation: Nucleic Acids Res. 2013 Jul;41(Web Server issue):W292-6
references.pmid: 23609546
references.citation: BMC Genomics. 2009 Apr 13;10:158
references.pmid: 19361343
references.citation: Nucleic Acids Res. 2002 Jul 15;30(14):3152-62
references.pmid: 12136097
references.citation: Brief Funct Genomic Proteomic. 2008 Jul;7(4):283-90
references.pmid: 18641417
references.citation: Cell Host Microbe. 2011 Nov 17;10(5):486-96
references.pmid: 22100164
references.citation: J Mol Biol. 2002 Jan 25;315(4):927-39
references.pmid: 11812158
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D290-301
references.pmid: 22127870
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712
references.citation: J Infect. 2009 Sep;59 Suppl 1:S17-24
references.pmid: 19766885
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Oct 1;66(Pt 10):1148-52
references.pmid: 20944204
references.citation: Structure. 2003 Nov;11(11):1453-9
references.pmid: 14604535
references.citation: PLoS One. 2007 Aug 13;3(8):e2950
references.pmid: 18670623
references.citation: J Infect Dis. 2005 Jun 15;191(12):2149-52
references.pmid: 15898002
references.citation: Vaccine. 2000 Dec 8;19 Suppl 1:S38-40
references.pmid: 11163461
references.citation: Vaccine. 2005 Mar 18;23(17-18):2035-41
references.pmid: 15755567
references.citation: Infect Immun. 2011 Jan;79(1):288-97
references.pmid: 21041497
references.citation: J Immunol. 2005 Aug 1;175(3):1813-9
references.pmid: 16034123
references.citation: Nucleic Acids Res. 2010 Jun;38(11):3570-81
references.pmid: 20176571
references.citation: Bioinformatics. 2011 Aug 1;27(15):2083-8
references.pmid: 21636590
references.citation: Int J Antimicrob Agents. 2007 Mar;29(3):233-9
references.pmid: 17204407
references.citation: J Bacteriol. 1988 Dec;170(12):5931-4
references.pmid: 2903859
references.citation: Curr Mol Med. 2008 Sep;8(6):497-509
references.pmid: 18781957
references.citation: Mol Microbiol. 1999 Feb;31(4):1275-81
references.pmid: 10096093
references.citation: Mol Microbiol. 2002 Sep;45(5):1389-406
references.pmid: 12207705
references.citation: Curr Opin Microbiol. 2002 Jun;5(3):338-42
references.pmid: 12057692
references.citation: Clin Infect Dis. 2001 Feb 15;32(4):552-8
references.pmid: 11181117
references.citation: Infect Immun. 2001 Mar;69(3):1593-8
references.pmid: 11179332
references.citation: J Infect Dis. 2004 Nov 1;190(9):1661-9
references.pmid: 15478073
references.citation: Microb Biotechnol. 2011 Mar;4(2):216-25
references.pmid: 21342467
references.citation: Acta Crystallogr D Biol Crystallogr. 2001 Nov;57(Pt 11):1747-51
references.pmid: 11679764
references.citation: J Mol Biol. 2004 May 14;338(5):1027-36
references.pmid: 15111065
references.citation: PLoS One. 2008;3(12):e4027
references.pmid: 19107199
references.citation: PLoS Comput Biol. 2009 Dec;5(12):e1000605
references.pmid: 20011109
references.citation: Mol Microbiol. 2007 Aug;65(4):1049-63
references.pmid: 17640279
references.citation: Microbes Infect. 2001 Nov-Dec;3(14-15):1345-52
references.pmid: 11755424
references.citation: Genome Biol. 2007;8(2):R22
references.pmid: 17313685
references.citation: Bioinformatics. 2012 Aug 1;28(15):2074-5
references.pmid: 22628523
references.citation: Comput Chem. 1994 Sep;18(3):269-85
references.pmid: 7952898
references.citation: Appl Environ Microbiol. 2001 Nov;67(11):5190-6
references.pmid: 11679344
references.citation: Mol Microbiol. 2010 Aug;77(4):1052-64
references.pmid: 20598082
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D71-5
references.pmid: 22102590
references.citation: Science. 1995 Jul 21;269(5222):400-3
references.pmid: 7618105
references.citation: Curr Microbiol. 2009 Oct;59(4):451-6
references.pmid: 19636617
references.citation: Bioinformatics. 2006 Feb 1;22(3):257-63
references.pmid: 16322048
references.citation: Nucleic Acids Res. 2005 Feb 08;33(3):880-92
references.pmid: 15701760
references.citation: PLoS Biol. 2004 Mar;2(3):E42
references.pmid: 15024411
references.citation: J Bacteriol. 2001 Oct;183(19):5709-17
references.pmid: 11544234
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D561-8
references.pmid: 21045058
references.citation: Prog Neurobiol. 2005 Sep-Oct;77(1-2):90-127
references.pmid: 16271823
references.citation: Gene. 1990 Jan 31;86(1):71-9
references.pmid: 2107126
references.citation: Mol Microbiol. 2001 Sep;41(6):1327-38
references.pmid: 11580837
references.citation: J Mol Med (Berl). 2010 Feb;88(2):103-7
references.pmid: 20162252
references.citation: Proteins. 2008 Jul;72(1):526-30
references.pmid: 18431750
references.citation: OMICS. 2011 Jul-Aug;15(7-8):431-8
references.pmid: 21348639
references.citation: J Struct Biol. 2006 Oct;156(1):2-11
references.pmid: 16828312
references.citation: PLoS One. 2012;7(7):e41202
references.pmid: 22848443
references.citation: Nature. 2001 May 3;411(6833):41-2
references.pmid: 11333967
references.citation: Cell. 2006 Feb 24;124(4):703-14
references.pmid: 16497582
references.citation: J Antimicrob Chemother. 2006 Aug;58(2):273-80
references.pmid: 16735427
references.citation: BMC Bioinformatics. 2010 Mar 08;11:119
references.pmid: 20211023
references.citation: J Mol Biol. 1986 Dec 20;192(4):753-65
references.pmid: 2438417
references.citation: PLoS One. 2011;6(8):e23626
references.pmid: 21886805
references.citation: Mol Cells. 2005 Jun 30;19(3):365-74
references.pmid: 15995353
references.citation: Genome Res. 2002 Jun;12(6):962-8
references.pmid: 12045149
references.citation: Mol Microbiol. 2005 Nov;58(4):1087-101
references.pmid: 16262792