Elucidation and conquest of S. aureus antibiotic resistance based on the whole genome sequence information

• Project/Area Number: 14021113
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: untendo University
• Principal Investigator: HIRAMATSU Keiichi Juntendo University, School of Medicine, Professor, 医学部, 教授 (10173262)
• Co-Investigator(Kenkyū-buntansha): 黒田 誠 順天堂大学, 医学部, 助手 (80317411)
• Project Period (FY): 2002 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥65,000,000 (Direct Cost: ¥65,000,000); Fiscal Year 2005: ¥15,000,000 (Direct Cost: ¥15,000,000); Fiscal Year 2004: ¥15,000,000 (Direct Cost: ¥15,000,000); Fiscal Year 2003: ¥16,000,000 (Direct Cost: ¥16,000,000); Fiscal Year 2002: ¥19,000,000 (Direct Cost: ¥19,000,000)
• Keywords: MRSA / Vancomycin resistance / SCC / oriC environ / clogging of peptidoglycan / Staphylococcus aureus / Staphylococcus haemolvticus / Whole eenome seauencine / トランスクリプトーム / 耐性菌 / SCCmec / 肺炎 / 敗血症

Research Abstract

1) Novel mechanism of glycopeptide resistance of Vancomycin-Intermediate S.aureus (VISA)
We used experimental and mathematical approach to prove Clogging mechanim of vancomycin resistance.
2) Indentification of novel genes which are responsible for glycopeptide resistance of Staphylococcus aureus. Two component systems vraSR and graSR are involved in the mechanism.
3) Identification of a novel chromosomal region " oriC environ" where alien genes are accumulated presumably by SCC (Staphylcoccal cassette chromosome)-mediated horizontal gene transfer. We proposed that the region is directly involved in the evolution and speciation of Staphylococcus species.

Research Products

• [Journal Article] Correlation between Reduced Daptomycin Susceptibility and Vancomycin Resistance in Vancomycin-Intermediate Staphylococcus aureus. (2006)
  • Author(s): Cui L, et al.
  • Journal Title: Antimicrob Agents Chemother. 50.3 Pages: 1079-1082
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Novel mechanism of antibiotic resistance originating in vancomycin-intermediate Staphylococcus aureus. (2006)
  • Author(s): Cui L, et al.
  • Journal Title: Antimicrob Agents Chemother. 50.2 Pages: 428-438
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cross-resistance of vancomycin-intermediate Staphylococcus aureus to daptomycin and vancomycin. (2006)
  • Author(s): Cui L, Tominaga E, Neoh Hui-min, Hiramatsu K.
  • Journal Title: Antimicrob Agents Chemother 50 Pages: 1079-1082
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Novel Mechanism of Antibiotic Resistance Originating in Vancomycin-Intermediate Staphylococcus aureus (2006)
  • Author(s): Cui L, Iwamoto A, Lian J-Q, Neoh Hui-min, Maruyama T, Horikawa Y, Hiramatsu K.
  • Journal Title: AAC 50 Pages: 428-438
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Correlation between Reduced Daptomycin Susceptibility and Vancomycin Resistance in Vancomycin-Intermediate Staphylococcus aureus (2006)
  • Author(s): Cui L
  • Journal Title: Antimicrob Agents Chemother 50(3) Pages: 1079-1082
• [Journal Article] Structural comparison of ten serotypes of staphylocoagulases in Staphylococcus aureus. (2005)
  • Author(s): Watanabe S, et al.
  • Journal Title: J Bacteriol. 187.11 Pages: 3698-3707
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Community-acquired methicillin-resistant Staphylococcus aureus, Uruguay. (2005)
  • Author(s): Ma XX, et al.
  • Journal Title: Emerg Infect Dis. 11.6 Pages: 973-976
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dissemination of methicillin-resistant staphylococci among healthy Japanese children. (2005)
  • Author(s): Hisata K, et al.
  • Journal Title: J Clin Microbiol. 43.7 Pages: 3364-3372
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Two heterogeneously vancomycin-intermediate clinical isolates of methicillin-sensitive and methicillin-resistant staphylococcus aureus in a Turkish university hospital : brief report of a surveillance study (2005)
  • Author(s): Torun MM, et al.
  • Journal Title: International Journal of Antimicrobial Agents 26.6 Pages: 508-510
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genetic Differentiation of Methicillin-Resistant Staphylococcus aureus Strains from Korea and Japan (2005)
  • Author(s): Kwan Soo Ko, et al.
  • Journal Title: Microbial Drug Resistance 11.3 Pages: 279-286
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] DNA micro array-based identification of genes associated with glycopeptide resistance in Staphylococcus aureus. (2005)
  • Author(s): Cui L, et al.
  • Journal Title: Antimicrob Agents Chemother 49.8 Pages: 3404-3413
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antibacterial Activity of Dipropofol and Related Compounds (2005)
  • Author(s): Ogata M, et al.
  • Journal Title: Biological ＆ Pharmaceutical Bulletin 28.6 Pages: 1120-1122
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Susceptibilities to antiseptic agents and distribution of antiseptic-resistance genes qacΑ/Βand smr of methicillin-resistant Staphylococcus aureus isolated in Asia during 1998 and 1999 (2005)
  • Author(s): Noguchi N, et al.
  • Journal Title: J Med Microbiol 54 Pages: 557-565
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Whole-genome sequencing of staphylococcus haemolyticus uncovers the extreme plasticity of its genome and the evolution of human-colonizing staphylococcal species. (2005)
  • Author(s): Takeuchi F.
  • Journal Title: J Bacteriol. 187.21 Pages: 7292-7308
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 臨床分離株に対するdoripenenの抗菌力 (2005)
  • Author(s): 桑原京子 他
  • Journal Title: 日本化学療法誌 53.S-1 Pages: 17-23
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Two heterogeneously vancomycin-intermediate clinical isolates of methicillin-sensitive and methicillin-resistant Staphylococcus aureus in a Turkish university hospital : brief report of a surveillance study. (2005)
  • Author(s): Torun MM, Bahar H, Demirci M, Altas K, Bagdatli Y, Kocazeybek B, Kapi M, Hiramatsu K.
  • Journal Title: Int J Antimicrob Agents. 26 Pages: 508-10
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Heterogeneous vancomy cin-resistant Staphylococcus aureus (hetero-VISA) in Singapore. (2005)
  • Author(s): Sng LH, Koh TH, Wang GC, Hsu LY, Kapi M, Hiramatsu K.
  • Journal Title: Int J Antimicrob Agents. 25 Pages: 177-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genetic differentiation of methicillin-resistant Staphylococcus aureus strains from Korea and Japan. (2005)
  • Author(s): Soo Ko K, Peck KR, Sup Oh W, Lee NY, Hiramatsu K, Song JH.
  • Journal Title: Microb Drug Resist. 11 Pages: 279-86
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] DNA microarray-based identification of genes associated with glycopeptide resistance in Staphylococcus aureus. (2005)
  • Author(s): Cui L, Lian JQ, Neoh HM, Reyes E, Hiramatsu K.
  • Journal Title: Antimicrob Agents Chemother. 49 Pages: 3404-13
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dissemination of methicillin-resistant staphylococci among healthy Japanese children. (2005)
  • Author(s): Hisata K, Kuwahara-Arai K, Yamanoto M, Ito T, Nakatomi Y, Cui L, Baba T, Terasawa M, Sotozono C, Kinoshita S, Yamashiro Y, Hiramatsu K.
  • Journal Title: J Clin Microbiol. 43 Pages: 3364-72
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Community-acquired methicillin-resistant Staphylococcus aureus,Uruguay. (2005)
  • Author(s): Ma XX, Galiana A, Pedreira W, Mowszowicz M, Christophersen I, Machiavello S, Lope L, Benaderet S, Buela F, Vincentino W, Albini M, Bertaux 0, Constenla I, Bagnulo H, Llosa L, Ito T, Hiramatsu K.
  • Journal Title: Emerg Infect Dis.Erratum in : Emerg Infect Dis 1111 Pages: 973-61329
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antibacterial activity of dipropofol and related compounds. (2005)
  • Author(s): Ogata M, Tutumimoto Sato K, Kunikane T, Oka K, Seki M, Urano S, Hiramatsu K, Endo T.
  • Journal Title: Biol Pharm Bull. 28 Pages: 1120-2
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Structural comparison of ten serotypes of staphylocoagulases in Staphylococcus aureus. (2005)
  • Author(s): Watanabe S, Ito T, Takeuchi F, Endo M, Okuno E, Hiramatsu K.
  • Journal Title: J Bacteriol. 187 Pages: 3698-707
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Susceptibilities to antiseptic agents and distribution of antiseptic-resistance genes qacA/B and smr of methicillin- resistant Staphylococcus aureus isolated in Asia during 1998 and 1999. (2005)
  • Author(s): Noguchi N, Suwa J, Narui K, Sasatsu M, Ito T, Hiramatsu K, Song JH.
  • Journal Title: J Med Microbiol. 54 Pages: 557-65
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Whole-genome sequencing of staphylococcus haemolyticus uncovers the extreme plasticity of its genome and the evolution of human-colonizing staphylococcal species. (2005)
  • Author(s): Takeuchi F, Watanabe S, Baba T, Yuzawa H, Ito T, Morimoto Y, Kuroda M, Cui L, Takahashi M, Ankai A, Baba S, Fukui S, Lee JC, Hiramatsu K.
  • Journal Title: J Bacteriol. 187 Pages: 7292-308
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Augmentation of the bactericidal activities of human cathelicidin CAP18/LL-37-derived antimicrobial peptides by amino acid substitutions. (2005)
  • Author(s): Nagaoka I, Kuwahara-Arai K, Tamura H, Hiramatsu K, Hirata M.
  • Journal Title: Inflamm Res. 54 Pages: 66-73
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Structural comparison of ten serotypes of staphylocoagulases in Staphylococcus aureus (2005)
  • Author(s): Watanabe S
  • Journal Title: J Bacteriol 187(11) Pages: 3698-3707
• [Journal Article] Community-acquired methicillin-resistant Staphylococcus aureus, Uruguay (2005)
  • Author(s): Ma XX
  • Journal Title: Emerg Infect Dis. 11(6) Pages: 973-976
• [Journal Article] Dissemination of methicillin-resistant staphylococci among healthy Japanese children (2005)
  • Author(s): Hisata K
  • Journal Title: J Clin Microbiol 43(7) Pages: 3364-3372
• [Journal Article] Two heterogeneously vancomycin-intermediate clinical isolates of methicillin-sensitive and methicillin-resistant Staphylococcus aureus in a Turkish university hospital : brief report of a surveillance study (2005)
  • Author(s): Torun MM
  • Journal Title: Int J Antimicrob Agents 26(6) Pages: 508-510
• [Journal Article] Genetic differentiation of methicillin-resistant Staphylococcus aureus strains from Korea and Japan (2005)
  • Author(s): Soo Ko K
  • Journal Title: Microb Drug Resist 11(3) Pages: 279-286
• [Journal Article] DNA microarray-based identification of genes associated with glycopeptide resistance in Staphylococcus aureus (2005)
  • Author(s): Cui L
  • Journal Title: Antimicrob Agents Chemother 49(8) Pages: 3404-3413
• [Journal Article] Antibacterial activity of dipropofol and related compounds (2005)
  • Author(s): Ogata M
  • Journal Title: Biol Pharm Bull 28(6) Pages: 1120-1122
• [Journal Article] Susceptibilities to antiseptic agents and distribution of antiseptic-resistance genes qacA/B and smr of methicillin-resistant Staphylococcus aureus isolated in Asia during 1998 and 1999 (2005)
  • Author(s): Noguchi N
  • Journal Title: J Med Microbiol 54(Pt 6) Pages: 557-565
• [Journal Article] Whole-genome sequencing of staphylococcus haemolyticus uncovers the extreme plasticity of its genome and the evolution of human-colonizing staphylococcal species (2005)
  • Author(s): Takeuchi F
  • Journal Title: J Bacteriol 187(21) Pages: 7292-7308
• [Journal Article] 臨床分離株に対するdoripenemの抗菌力 (2005)
  • Author(s): 桑原京子
  • Journal Title: 日本化学療法雑誌 53(S-1) Pages: 17-23
• [Journal Article] Novel Mechanism of Antibiotic Resistance Originating in Vancomycin-Intermediate Staphylococcus aureus (2005)
  • Author(s): Cui L
  • Journal Title: Antimicrob Agents Chemother 50(2) Pages: 428-438
• [Journal Article] Advance in Vancomycin Resistance : Research in Staphylococcus aureus (2005)
  • Author(s): Hiramatsu K. et al.
  • Journal Title: Anti-infective Drug Discovery (in press)
• [Journal Article] Genetic characterization of methicillin-resistant Staphylococcus aureus. (2004)
  • Author(s): Hiramatsu K, Watanabe S, Takeuchi F, Ito T, Baba T.
  • Journal Title: Vaccine. 22 Suppl
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Asian Network for Surveillance of Resistant Pathogens Study Group. Emergence in Asian countries of Staphylococcus aureus with reduced susceptibility to vancomycin. (2004)
  • Author(s): Song JH, Hiramatsu K, Suh JY, Ko KS, Ito T, Kapi M, Kiem S, Kim YS, Oh WS, Peck KR, Lee NY
  • Journal Title: Antimicrob Agents Chemother 48 Pages: 4926-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Has vancomycin-resistant Staphylococcus aureus started going it alone? (2004)
  • Author(s): Hiramatsu K, Cui L, Kuwahara-Arai K.
  • Journal Title: Lancet. 364 Pages: 565-6
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Novel type V staphylococcal cassette chromosome mec driven by a novel cassette chromosome recombinase, ccrC. (2004)
  • Author(s): Ito T, Ma XX, Takeuchi F, Okuma K, Yuzawa H, Hiramatsu K.
  • Journal Title: Antimicrob Agents Chemother 48 Pages: 2637-51
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nucleotide substitutions in Staphylococcus aureus strains, Mu50, Mu3, and N315. (2004)
  • Author(s): Ohta T, Hirakawa H, Morikawa K, Maruyama A, Inose Y, Yamashita A, Oshima K, Kuroda M, Hattori M, Hiramatsu K, Kuhara S, Hayashi H.
  • Journal Title: DNA Res. 29 Pages: 51-6
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Emergence in Asian Countries of Staphylococcus aureus with Reduced Susceptibility to Vancomycin. (2004)
  • Author(s): Song JH. et al.
  • Journal Title: Antimicrob Agents Chemother. 48(12) Pages: 4926-4928
• [Journal Article] Novel type V staphylococcal cassette chromosome mec driven by a novel cassette chromosome recombinase, ccrC. (2004)
  • Author(s): Ito T.et al.
  • Journal Title: Antimicrob Agents Chemother. 48(7) Pages: 2637-2651
• [Journal Article] Has vancomycin-resistant Staphylococcus aureus started going it alone? (2004)
  • Author(s): Hiramatsu K. et al.
  • Journal Title: Lancet 364(9434) Pages: 565-566
• [Journal Article] Vancomycin heteroresistance in methicillin-resistant Staphylococcus aureus, Taiwan. (2004)
  • Author(s): Wang JL. et al.
  • Journal Title: Emerg Infect Dis. 10(9) Pages: 1702-1704
• [Journal Article] Genome sequencing and annotation : an overview. (2004)
  • Author(s): Kuroda M. et al.
  • Journal Title: Methods Mol Biol. 266 Pages: 29-45
• [Journal Article] Genetic characterization of methicillin-resistant Staphylococcus aureus. (2004)
  • Author(s): Hiramatsu K. et al.
  • Journal Title: Vaccine 22
• [Publications] Ito, T., et al.: "Insights on Antibiotic Resistance of Staphylococcus aureus from its Whole Genome : Genomic Island SCC"Drug Res.Updates. 6. 41-52 (2003)
• [Publications] Cui, L., et al.: "Cell Wall Thickening Is a Common Feature of Vancomycin Resistance in Staphylococcus aureus"J.Clin.Microbiol.. 41. 5-14 (2003)
• [Publications] Yoshida, R., et al.: "Physiological and molecular analysis of a mecA-negative Staphylococcus aureus clinical strain that expresses heterogeneous methicillin resistance"J Antimicrob Chemother. 51. 247-255 (2003)
• [Publications] Katayama, Y., et al.: "Identification in a methicillin-susceptible Staphylococcus hominis of an active primordial mobile genetic element for the staphylococcal cassette chromosome mec (SCCmec) of methicillin-resistant Staphylococcus aureus."J.Bacteriol.. 185. 2711-2722 (2003)
• [Publications] Isnansetyo, A., et al.: "Antibacterial activity of 2,4-diacetylphloroglucinol (DAPG) produced by Pseudomonas sp. AMSN isolated from a marine alga, against vancomycin-resistant Staphylococcus aureus (VRSA)"Int J Antimicrob Agents. 22. 545-547 (2003)
• [Publications] Kuroda, M., et al.: "Two-component system VraSR positively modulates the regulation of cell wall biosynthesis pathway in Staphylococcus aureus"Molecular Microbiol. 49. 807-821 (2003)
• [Publications] Cui, L.et al.: "Vancomycin-resistant Staphylococcus aureus."Horizon Scientific Press. 340 (2003)
• [Publications] Kuroda, M. et al.: "Genomics, Proteomics and Clinical Bacteriology."Humana Press. 320 (2004)
• [Publications] Baba, T. et al.: "The Genome of Staphylococcus aureus."Eliis Harwood (In press). (2004)
• [Publications] Hiramatsu, K.: "Elucidation of the mechanism of antibiotic resistance acquisition of methicillin-resistant Staphylococcus aureus (MRSA) and determination of its whole genome nucleotide sequence"Jap Med Assoc J. (In press). (2004)
• [Publications] Hiramatsu, K., et al.: "The Staphylococcus aureus model"ASM Press (In Press). (2004)
• [Publications] Hiramatsu, K.et al.: "Molecular Genetics of Methicillin-Resistant Staphylococcus aureus"Int J Med Microbiol. 292. 67-74 (2002)
• [Publications] Yashida, R.et al.: "Physiological and molecular analysis of a mecA-negative Staphylococcus aureus clinical strain that expresses heterogeneous methicillin resistance"J Antimicrob Chemother. 51. 247-255 (2003)
• [Publications] Baba, T.et al.: "Genome and virulence determinants of high virulence community-acquired MRSA"Lancet.. 359. 1819-1827 (2002)
• [Publications] van der Zwet W.C.et al.: "Nosocomial spread of a Staphylococcus capitis strain with hetero-resistance to vancmycin in a neonatal intensive care unit"J.Clin.Microbiol. 40. 2520-2525 (2002)
• [Publications] Ma X X.et al.: "A novel type of staphylococcal cassette chromsome mec (SCCmec) identified in community-acquired methicillin-resistant Staphylococcus aureus strains"Antimicrob.Agents.Chemother. 46. 1147-1152 (2002)
• [Publications] Okuma K.et al.: "Dissemination of New MRSA Clones in the Community"J.Clin.Microbiol. 40. 4289-4294 (2002)
• [Publications] Daum, R.S.et al.: "A novel methicillin-resistance cassette in community-acquired methicillin-resistant Staphylococcus aureus isolates of diverse genetic"J Infect Dis.. 186. 1344-1347 (2002)
• [Publications] Hiramatsu, K.et al.: "New trends in Staphylococcus aureus infections : glycopeptide resistance in hospital and methicillin resistance in community"Current Opinion in Infections Diseases. 15. 407-413 (2002)
• [Publications] Kuroda, M.et al.: "Genome sequencing and annotation : an overview in Johnson, A.,and Woodford, N., et.,Genomics, Proteomics and Clinical Bacteriology"Humana Press.(in press).
• [Publications] Hiramatsu, K.et al.: "Application of Genomic Information to the Diagnosis, Management and Control of Bacterial Infections : The Staphylococcus aureus model"ASM press(in press).