Enzymatic synthesis and characterization of aryl iodides of some phenolic acids with enhanced antibacterial properties.

Phenolic acids represent a class of drugs with mild antibacterial properties. We have synthesized iodinated gallic and ferulic acids and together with commercially available iodinated forms of salicylic acids studied their cytotoxicity, bacteriostatic and anti-virulence action. Out of these, iodogallic acid had lowest minimal inhibitory concentration (MIC) against Staphylococcus aureus (MIC = 0.4 mM/118.8 μg/ml). Yet, it had strong effect on erythrocyte membrane lipid ordering and on α-hemolysin secretion by the bacteria at lower non-bacteriostatic and non-cytotoxic concentrations (<0.1 mM). Iodogallic acid formed static complexes with α-hemolysin in solutions (logKb = 4.69 ± 0.07) and inhibited its nano-pore conduction in artificial lipid bilayers (IC50 = 37.9 ± 5.3 μM). These effects of iodogallic acid converged on prevention of hemolysis induced by α-hemolysin (IC50 = 41.5 ± 4.2 μM) and pointed to enhanced and diverse anti-virulence properties of some aryl iodides. The analysis of molecular surface electrostatic charge distribution, molecular hydrophilicity, electronegativity, and dipole moment of studied compounds suggested the importance of the number of hydroxyl groups and their proximity to iodine in anti-virulence activity manifestation. In iodogallic acid, charge redistribution resulted in higher hydrophilicity without concomitant change in overall molecular electronegativity and dipole moment compared to non-iodinated gallic acid. This study shows new directions for the development of antibacterial/antivirulence therapeutics.