TY - JOUR
T1 - Minimum structural requirements for cell membrane leakage-mediated anti-MRSA activity of macrocyclic bis(bibenzyl)s
AU - Fujii, Kana
AU - Morita, Daichi
AU - Onoda, Kenji
AU - Kuroda, Teruo
AU - Miyachi, Hiroyuki
N1 - Funding Information:
This work was supported in part by a grant for the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science, and Technology , Japan, and a Grant-in-aid for Scientific Research (B) (grant number 26293027 to H.M.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). We also thank the SC-NMR Laboratory of Okayama University for NMR measurements.
Publisher Copyright:
© 2016 Elsevier Ltd. All rights reserved.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Macrocyclic bis(bibenzyl)-type phenolic natural products, found exclusively in bryophytes, exhibit potent antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Here, in order to identify the minimum essential structure for cell membrane leakage-mediated anti-MRSA activity of these compounds, we synthesized acyclic fragment structures and evaluated their anti-MRSA activity. The activities of all of the acyclic fragments tested exhibited similar characteristics to those of the macrocycles, i.e., anti-MRSA bactericidal activity, an enhancing effect on influx and efflux of ethidium bromide (EtBr: fluorescent DNA-binder) in Staphylococcus aureus cells, and bactericidal activity towards a Staphylococcus aureus strain resistant to 2-phenoxyphenol (4). The latter result suggests that they have a different mechanism of action from 4, which is a FabI inhibitor previously proposed to be the minimum active fragment of riccardin-type macrocycles. Thus, cyclic structure is not a necessary condition for cell membrane leakage-mediated anti-MRSA activity of macrocyclic bis(bibenzyl)s.
AB - Macrocyclic bis(bibenzyl)-type phenolic natural products, found exclusively in bryophytes, exhibit potent antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Here, in order to identify the minimum essential structure for cell membrane leakage-mediated anti-MRSA activity of these compounds, we synthesized acyclic fragment structures and evaluated their anti-MRSA activity. The activities of all of the acyclic fragments tested exhibited similar characteristics to those of the macrocycles, i.e., anti-MRSA bactericidal activity, an enhancing effect on influx and efflux of ethidium bromide (EtBr: fluorescent DNA-binder) in Staphylococcus aureus cells, and bactericidal activity towards a Staphylococcus aureus strain resistant to 2-phenoxyphenol (4). The latter result suggests that they have a different mechanism of action from 4, which is a FabI inhibitor previously proposed to be the minimum active fragment of riccardin-type macrocycles. Thus, cyclic structure is not a necessary condition for cell membrane leakage-mediated anti-MRSA activity of macrocyclic bis(bibenzyl)s.
KW - Cell membrane leakage
KW - Macrocyclic bis(bibenzyl) derivative
KW - Membrane
KW - Methicillin resistance
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=84961150517&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961150517&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2016.03.033
DO - 10.1016/j.bmcl.2016.03.033
M3 - Article
C2 - 26995530
AN - SCOPUS:84961150517
VL - 26
SP - 2324
EP - 2327
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 9
ER -