Inhibition of cyclic diadenylate cyclase, DisA, by polyphenols.

Clement Opoku-Temeng,Herman O. Sintim

doi:10.1038/srep25445

Clement Opoku-Temeng, Herman O. Sintim

Open Access

https://doi.org/10.1038/srep25445

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Abstract

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.

Highlights

Cyclic di-AMP has emerged as an important signaling molecule that controls a myriad of functions, including cell wall homeostasis in different bacteria
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
TF1, TF2B and TF3 contain the same theaflavin moiety and only differ by the number of attached gallate units (TF1 contains no gallates; TF2B contains one gallate and TF3 contains two gallates); inhibition was observed to increase from TF1 to TF3

Summary

Introduction

Cyclic di-AMP has emerged as an important signaling molecule that controls a myriad of functions, including cell wall homeostasis in different bacteria. Just like the analogous c-di-GMP, c-di-AMP is emerging as an important signaling second messenger in several bacteria and has been found to regulating several physiological processes including but not limited to cell wall homeostasis[5,6], fatty acid metabolism[7], cell size regulation[8] and virulence[5] (Fig. 1). The intracellular levels of c-di-AMP are tightly regulated by two opposing enzymes: diadenylate cyclases (DAC), which synthesize c-di-AMP from two molecules of ATP/ADP and phosphodiesterases (PDE), which degrade c-di-AMP into pApA or AMP10–13 This tight regulation is important in keeping an optimal intracellular c-di-AMP concentration as overproduction or underproduction of the signaling molecule has been observed to cause interesting changes in bacteria physiology[5,8,14]. Peptidoglycan synthesis or remodeling, it is likely that inhibitors of c-di-AMP synthesis or degradation could be utilized as antibacterial agents or used in synergy with traditional antibiotics

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