期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 13, 页码 3309-3316出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.04.047
关键词
Isoplagiochin; Methicillin resistance; Membrane; Cell membrane damage; Structure-activity relationship
资金
- Drug Discovery for Intractable Infectious Diseases Project
- Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
- Grant for Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan
- Terumo Foundation
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT) [A26293027]
- Grants-in-Aid for Scientific Research [25460157] Funding Source: KAKEN
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. (C) 2015 Elsevier Ltd. All rights reserved.
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