Mode of Action of Microbial Anti-MRSA Agents

• Tomoda Hiroshi

  Graduate School of Pharmaceutical Sciences, Kitasato University

Bibliographic Information

Other Title

• 微生物由来の抗ＭＲＳＡ剤の作用機構の解析
• ビセイブツ ユライ ノ コウMRSAザイ ノ サヨウ キコウ ノ カイセキ

Abstract

  Methicillin-resistant Staphylococcus aureus (MRSA) is known as a major nosocomial pathogen that has also developed resistance to many antibiotics. Moreover, MRSA resistance to a last-resort antibiotic, vancomycin, has been reported. Therefore, new anti-infectious agents to prevent and treat MRSA infection are needed. Based on this background, our group has focused on the discovery of new microbial agents active against MRSA infection. Viridicatumtoxin and spirohexaline, produced by Penicillium sp. FKI-3368, were isolated as inhibitors of undecaprenyl pyrophosphate (UPP) synthase of Staphylococcus aureus, which was involved in cell wall synthesis. Viridicatumtoxin and spirohexaline with a pentacyclic spiro skeleton inhibited UPP synthase activity with an IC₅₀ value of 4.0 and 9.0 μM, respectively. Actually, the growth of gram-positive bacteria including MRSA was strongly inhibited by the compounds. Our computational modeling experiments indicated that spirohexaline A was inserted into the substrate pocket of UPP synthase and interacted with Glu₈₈ via a carbamoyl group of the compound, with Ala₇₆, Met₅₄ and Asn₃₅ via three hydroxyl groups, and with certain hydrophobic amino acids via a spiro ring. Cyslabdan, produced by Streptomyces sp. K04-0144, was isolated as a potentiator of β-lactam imipenem activity against MRSA. The compound consisted of a labdan skeleton and an N-acetylcysteine. Cyslabdan potentiated imipenem activity by over 1000 fold, drastically reducing the MIC value of imipenem against MRSA from 16 to 0.03 μg/mL. The binding proteins of cyslabdan were investigated in the lysate of MRSA to identify FemA, which was involved in the formation of the pentaglycine interpeptide bridge in MRSA peptidoglycan.<br>

Journal

• YAKUGAKU ZASSHI

  YAKUGAKU ZASSHI 132 (1), 37-44, 2012

  The Pharmaceutical Society of Japan

Keywords

• methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)
• mode of action
• cyslabdan
• spirohexaline
• antibiotics
• chemical biology

Details

• CRID: 1390282681104602112
• NII Article ID: 130001871960
• NII Book ID: AN00284903
• DOI: 10.1248/yakushi.132.37
• ISSN: 13475231
• ISSN: 00316903
• NDL BIB ID: 023456547
• Web Site: http://id.ndl.go.jp/bib/023456547
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I023456547
• Web Site: http://www.jstage.jst.go.jp/article/yakushi/132/1/132_1_37/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2012143220
• Text Lang: ja
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed