Antibiotic resistance has become an increasingly difficult problem for the world’s healthcare communities since the dawn of the antibiotic age. One of the most well-known and troublesome species is Staphylococcus aureus, specifically methicillin-resistant S. aureus (MRSA) strains. The Centers for Disease Control and Prevention recognizes MRSA as a serious threat, and as such, new tactics, including the adjuvant approach, are needed to effectively treat these infections. Recently discovered was the synergy of a clerodane diterpene with oxacillin against MRSA. The natural product has shown efficacy against several clinically relevant MRSA strains, and preliminary cytotoxicity studies suggest it possesses only mild toxicity against mammalian cells. To validate the potential of this molecule, we developed a synthetic route that accesses the enantiopure natural product in 15 steps from a common Wieland-Miescher ketone and allows for deep structural modifications. Additionally, the molecule’s stereochemistry, and that of its epimer, was assigned unambiguously via single crystal X-ray diffraction. With access to the natural product established, we are now conducting structure-activity relationship investigations to improve efficacy, elucidate a mode of action, and ultimately develop the scaffold as a novel area of chemical space for synergy with β-lactam antibiotics.

Analogs of a clerodane diterpene as potentiators of β-lactams against methicillin-resistant Staphylococcus aureus

ACS Spring 2022

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