Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
Design, Synthesis and Structure-activity Relationship Study of a Series of Bis(bibenzyl)-type Natural Products, Riccardin C Derivatives, as Candidate Anti-MRSA Agents
Hiroyuki MiyachiTeruo Kuroda
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2018 Volume 138 Issue 12 Pages 1537-1547


We previously showed that a naturally occurring macrocyclic bis(bibenzyl) derivative, riccardin C (RC), exhibits antibacterial activity towards methicillin-resistant Staphylococcus aureus (MRSA), with a potency comparable to that of the clinically used drug vancomycin. Here, we synthesized a series of RC derivatives to explore the structure-activity relationships (SAR). The SAR results clearly indicated that the number and positions of the phenolic hydroxyl groups are primary determinants of the anti-MRSA activity. Pharmacological characterization of the macrocyclic bis(bibenzyl) derivatives, together with fragment compounds and their dimers, indicated that the macrocycles and the fragment compounds elicit anti-MRSA activity with different mechanism(s) of action. The macrocyclic bis(bibenzyl)s are bactericidal, while the fragment compounds are bacteriostatic, showing only weak bactericidal activity. Treatment with a macrocyclic bis(bibenzyl) derivative significantly changed the intracellular Na+ and K+ concentrations of Staphylococcus aureus, and transmission electron microscopy revealed that treated cells developed intracellular lamellar mesosomal-like structures. These results indicated that the macrocyclic compound directly damages the gram-positive bacterial membrane, resulting in increased permeability.

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© 2018 The Pharmaceutical Society of Japan
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