Insights on Zosteric Acid Analogues Activity Against <i>Candida albicans</i> Biofilm Formation

Zosteric acid (ZA), or <i>p</i>-(sulphooxy)-cinnamic acid, is a secondary metabolite of the seagrass Zostera marina able to reduce biofilm formation of a wide range of bacteria and fungi, through a nonbiocidal mode of action. However, the lack of information concerning the specific chemical structural elements responsible for ZA's antibiofilm activity has hindered the scaling up of this green-based technology for real applications. In this study, a small library of molecules based on ZA scaffold diversity was screened against the eukaryotic fungus Candida albicans, in order to identify the key chemical features of ZA necessary for inhibiting fungal biofilm at sublethal concentrations. Results, supported by multivariate statistical analysis, revealed that the presence of (i) the <i>trans</i> (<i>E</i>) double bond, (ii) the free carboxylic group in the side chain, and (iii) the <i>para</i> substitution with a hydroxyl group were all instrumental for maintaining the antibiofilm activity of the molecules. Additionally, molecular modeling studies suggested that the best performing derivatives interacted with NADP-(H) quinone oxidoreductase, influencing the microbial redox balance.