Inhibition of cyclic diadenylate cyclase, DisA, by polyphenols

Cyclic di-AMP has emerged as an important signaling molecule that controls a myriad of functions, including cell wall homeostasis in different bacteria. Polyphenols display various biological activities and tea polyphenols in particular have been shown to possess among other properties antioxidant and antibacterial activities. Certain tea polyphenols, such as catechin and epigallocatechin gallate, have been used to augment the action of traditional antibiotics that target the cell wall. Considering the expanding role played by cyclic dinucleotides in bacteria, we investigated whether the action of polyphenols on bacteria could be due in part to modulation of c-di-AMP signaling. Out of 14 tested polyphenols, tannic acid (TA), theaflavin-3'-gallate (TF2B) and theaflavin-3,3'-digallate (TF3) exhibited inhibitory effects on B. subtilis c-di-AMP synthase, DisA. TF2B and TF3 specifically inhibited DisA but not YybT (a PDE) whilst TA was more promiscuous and inhibited both DisA and YybT.