Synthesis and evaluation of cadiolide analogues as inhibitors of bacterial biofilm formation

Abstract

Bacterial biofilm infections pose a major clinical challenge due to the ability of biofilms to resist high levels of conventional antibiotics. In the present study, we describe the synthesis and biofilm inhibiting properties of nine new butenolides related to the cadiolide family of marine antibiotics. Eight new cadiolide analogues were synthesized using oxazole−ynone Diels−Alder cycloaddition/cycloreversion as the key step. Their effects on bacterial growth and biofilm formation were investigated against a range of Gram-positive and Gram-negative bacteria, namely Staphylococcus aureus, Enterococcus faecalis, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. The cadiolide analogues strongly inhibited biofilm formation of the two Gram-positive bacteria (S. aureus and E. faecalis) at concentrations as low as 0.3 μg mL−1 and 0.5 μg mL−1, respectively. The identification of synthetic cadiolides with potent biofilm-inhibiting capabilities opens a new avenue for therapeutic interventions and highlights the potential of this class of compounds for antimicrobial drug development.