A Clerodane Diterpene from Callicarpa americana Resensitizes Methicillin-Resistant Staphylococcus aureus to β‑Lactam Antibiotics

The rise of antibiotic resistance presents a significant healthcare challenge and precludes the use of many otherwise valuable antibiotics. One potential solution to this problem is the use of antibiotics in combination with resistance-modifying agents, compounds that act synergistically with existing antibiotics to resensitize previously resistant bacteria. In this study, 12­(S),16ξ-dihydroxycleroda-3,13-dien-15,16-olide, a clerodane diterpene isolated from the medicinal plant Callicarpa americana, was found to synergize with oxacillin against methicillin-resistant Staphylococcus aureus. This synergy was confirmed by checkerboard (fractional inhibitory concentration index (FICI) = 0.125) and time-kill assays, with a subinhibitory dose of 12­(S),16ξ-dihydroxycleroda-3,13-dien-15,16-olide causing the effective concentration of oxacillin to fall below the susceptibility breakpoint for S. aureus, a >32-fold decrease in both cases.