Synthesis and Evaluation of Troponoids as a New Class of Antibiotics

Novel antibiotics are urgently needed. The troponoids [tropones, tropolones, and α-hydroxytropolones (α-HT)] can have anti-bacterial activity. We synthesized or purchased 92 troponoids and evaluated their antibacterial activities against Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. Preliminary hits were assessed for minimum inhibitory concentrations (MIC<sub>80</sub>) and cytotoxicity (CC<sub>50</sub>) against human hepatoma cells. Sixteen troponoids inhibited S. aureus/E. coli/A. baumannii growth by ≥80% growth at <30 μM with CC<sub>50</sub> values >50 μM. Two selected tropolones (<b>63</b> and <b>285</b>) inhibited 18 methicillin-resistant S. aureus (MRSA) strains with similar MIC<sub>80</sub> values as against a reference strain. Two selected thiotropolones (<b>284</b> and <b>363</b>) inhibited multidrug-resistant (MDR) E. coli with MIC<sub>80</sub> ≤30 μM. One α-HT (<b>261</b>) inhibited MDR-A. baumannii with MIC<sub>80</sub> ≤30 μM. This study opens new avenues for development of novel troponoid antibiotics to address the critical need to combat MDR bacterial infections.