Synthesis and Evaluation of Troponoids as a New Class of Antibiotics

Abstract

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 (MIC₈₀) and cytotoxicity (CC₅₀) against human hepatoma cells. Sixteen troponoids inhibited S. aureus/E. coli/A. baumannii growth by ≥80% growth at <30 μM with CC₅₀ values >50 μM. Two selected tropolones (63 and 285) inhibited 18 methicillin-resistant S. aureus (MRSA) strains with similar MIC₈₀ values as against a reference strain. Two selected thiotropolones (284 and 363) inhibited multidrug-resistant (MDR) E. coli with MIC₈₀ ≤30 μM. One α-HT (261) inhibited MDR-A. baumannii with MIC₈₀ ≤30 μM. This study opens new avenues for development of novel troponoid antibiotics to address the critical need to combat MDR bacterial infections.

Figure 1

Structures of (A) tropone, (B) tropolone, and (C) α-HT. Structures for all compounds tested are in Figure S1.

Figure 2

Time-killing curves for compounds 63 and 285 against S. aureus (ATCC 29213) and for 284 and 363 against E. coli (ATCC 35218).