Anti-MRSA activity of isoplagiochin-type macrocyclic bis(bibenzyl)s is mediated through cell membrane damage

Kenji Onoda, Hiromi Sawada, Daichi Morita, Kana Fujii, Hiroaki Tokiwa, Teruo Kuroda, Hiroyuki Miyachi

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10 Citations (Scopus)

Abstract

Abstract We synthesized three geometrical isomers of a macrocyclic bis(bibenzyl) based on isoplagiochin, a natural product isolated from bryophytes, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The isomer containing a 1,4-linked ring (5) showed only weak activity, whereas the isomers containing a 1,3-linked (6) or 1,2-linked (7) C ring showed potent anti-MRSA activity. Molecular dynamics calculations indicated that these differences are probably due to differences in the conformational flexibility of the macrocyclic ring; the active compounds 6 and 7 were more rigid than 5. In order to understand the action mechanism of anti-MRSA activity, we investigated the cellular flux of a fluorescent DNA-binder, ethidium bromide (EtBr), in the presence and absence of these macrocycles. The active compound 6 increased the levels of EtBr inflow and outflow in S. aureus cells, as did our potent anti-MRSA riccardin derivative (4), indicating that these compounds increased the permeability of the cytoplasmic membrane. Inactive 5 had no effect on EtBr inflow or outflow. Furthermore, compound 6 abrogated the normal intracellular concentration gradients of Na+ and K+ in S. aureus cells, increasing the intracellular Na+ concentration and decreasing the K+ concentration, while 5 had no such effect. These results indicate that anti-MRSA-active macrocyclic bis(bibenzyl) derivatives directly damage the gram-positive bacterial membrane, resulting in increased permeability.

Original languageEnglish
Article number12259
Pages (from-to)3309-3316
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number13
DOIs
Publication statusPublished - 2015

Keywords

  • Cell membrane damage
  • Isoplagiochin
  • Membrane
  • Methicillin resistance
  • Structure-activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Onoda, K., Sawada, H., Morita, D., Fujii, K., Tokiwa, H., Kuroda, T., & Miyachi, H. (2015). Anti-MRSA activity of isoplagiochin-type macrocyclic bis(bibenzyl)s is mediated through cell membrane damage. Bioorganic and Medicinal Chemistry, 23(13), 3309-3316. [12259]. https://doi.org/10.1016/j.bmc.2015.04.047