Anti-MRSA activity of isoplagiochin-type macrocyclic bis(bibenzyl)s is mediated through cell membrane damage.
Bioorg Med Chem
; 23(13): 3309-16, 2015 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-25999206
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Bibenzilas
/
Membrana Celular
/
Permeabilidade da Membrana Celular
/
Staphylococcus aureus Resistente à Meticilina
/
Antibacterianos
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article