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

Research output: Contribution to journalArticle

6 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

Fingerprint

Ethidium
Cell membranes
Methicillin-Resistant Staphylococcus aureus
Isomers
Cell Membrane
Derivatives
Membranes
Methicillin
Biological Products
Binders
Staphylococcus aureus
Molecular dynamics
Permeability
Fluxes
Bryophyta
DNA
Molecular Dynamics Simulation

Keywords

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

ASJC Scopus subject areas

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

Cite this

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

Anti-MRSA activity of isoplagiochin-type macrocyclic bis(bibenzyl)s is mediated through cell membrane damage. / Onoda, Kenji; Sawada, Hiromi; Morita, Daichi; Fujii, Kana; Tokiwa, Hiroaki; Kuroda, Teruo; Miyachi, Hiroyuki.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 13, 12259, 2015, p. 3309-3316.

Research output: Contribution to journalArticle

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, vol. 23, no. 13, 12259, pp. 3309-3316. https://doi.org/10.1016/j.bmc.2015.04.047
Onoda, Kenji ; Sawada, Hiromi ; Morita, Daichi ; Fujii, Kana ; Tokiwa, Hiroaki ; Kuroda, Teruo ; Miyachi, Hiroyuki. / Anti-MRSA activity of isoplagiochin-type macrocyclic bis(bibenzyl)s is mediated through cell membrane damage. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 13. pp. 3309-3316.
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AB - 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.

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