Concise Synthesis of Simplified Aogacillin Analogs Reveals Innate Reactivity and Synergy with Aminoglycosides

Abstract

Aogacillins (AOGs) A-B, two diastereomeric natural products isolated from Simplicillium sp. FKI-5985, were reported to have potent synergism with aminoglycoside antibiotics. Herein, we show that structural simplification expedites the synthesis of AOG analogs in 3-4 steps. Further, we demonstrate that these compounds irreversibly trap cysteine nucleophiles at an electrophilic enone warhead but are also susceptible to [4+2] cycloadditions. Therefore, strategically designed AOG analogs were constructed to mitigate side reactivity and sensitize MRSA to aminoglycosides at sub-MIC concentrations.