Selection and Identification of Novel Antibacterial Agents against Planktonic Growth and Biofilm Formation of Enterococcus faecalis

Abstract

YycFG, one of the two-component systems involved in the regulation of biofilm formation, has attracted increasing interest as a potential target of antibacterial and antibiofilm agents. YycG inhibitors for Staphylococcus aureus and Staphylococcus epidermidis have been developed, but Enterococcus faecalis remains underexplored. Herein, we selected and identified novel candidate molecules against E. faecalis targeting histidine kinase YycG using high-throughput virtual screening; six molecules (compound-16, -30, -42, -46, -59, and -62) with low cytotoxicity toward mammalian cells were verified as potential YycG inhibitors through an autophosphorylation test and binding kinetics. Compound-16 inhibited planktonic cells of E. faecalis, including the vancomycin- or linezolid-resistant strains. In contrast, compound-62 did not affect planktonic growth but significantly inhibited biofilm formation in static and dynamic conditions. Compound-62 combined with ampicillin could synergistically eradicate the biofilm-embedded viable bacteria. The study demonstrates that YycG inhibitors may be valuable approaches for the development of novel antimicrobial agents for difficult-to-treat bacterial infections.

Development of 2‐Alkyl‐5‐((phenylsulfonyl)oxy)‐1H‐indole‐3‐carboxylate Derivatives as Potential Anti‐Biofilm Agents

“…The reported YycG HK inhibitors included three different classes of chemical structures: indoles, 2,4‐thiazolidinediones, and pyrrolidones. Among these inhibitors, a typical compound 16, which had an indole core with benzenesulfonyl and ester groups, showed effectively antibacterial and anti‐biofilm activity, exhibited low cytotoxicity on mammalian cells and was not hemolytic [18] (Scheme 1). Compared with vancomycin and ampicillin, compound 16 had a better inhibition effect on E. faecalis .…”

“…According to the docking test between compound 16 and YycG protein which had been studied by Yu et al., [18] it was found that the inhibitor had one hydrogen bond acceptor, hydrogen bonding to Asn501, Ser571, and Lys572; two hydrophobic groups, hydrophobic groups fit into two hydrophobic cavities including Leu536, Ile538, Tyr509 and Phe594, Val546, Phe547 amino acid residues locating inside and outside YycG protein, respectively. In this article, a series of 2‐alkyl‐5‐((phenylsulfonyl)oxy)‐1 H ‐indole‐3‐carboxylate derivatives with benzenesulfonyl and ester groups were designed and synthesized to expect to obtain several targeted histidine kinase inhibitors with good anti‐bacterial and anti‐biofilm activities.…”

Derivatization of Dihydropyrrolidone-Thiadiazole Heterocyclic Compounds and an Evaluation of their Antibacterial and Anti-Biofilm Activities

“…9 Small molecular inhibitors can inhibit the autophosphorylation of YycG by binding to the HATPase_c domain or HisKA domain, thereby inhibiting bacterial growth and biofilm formation. 10 Hence, histidine kinase (HK) of bacterial two-component systems becomes a potential antibacterial target. 11 Multiple reports have demonstrated the effective development of antimicrobial molecules against B. subtilis (Walkmycin C), 12 S. aureus (Aranorosinol B), 13 and E. faecalis (Waldiomycin) 14 by targeting YycG histidine kinase.…”

“…11 Multiple reports have demonstrated the effective development of antimicrobial molecules against B. subtilis (Walkmycin C), 12 S. aureus (Aranorosinol B), 13 and E. faecalis (Waldiomycin) 14 by targeting YycG histidine kinase. In our previous study, some novel inhibitors of YycG histidine kinase including thiazolidones, 15 thiazolopyrimidinones, 16 indoles, and pyrrolidones 10 had been reported, which had potential values as leads for developing new antibiotics. Among these inhibitors, compound 62 10 (Fig.…”

“…In our previous study, some novel inhibitors of YycG histidine kinase including thiazolidones, 15 thiazolopyrimidinones, 16 indoles, and pyrrolidones 10 had been reported, which had potential values as leads for developing new antibiotics. Among these inhibitors, compound 62 10 (Fig. 1) has a core of the Dihydropyrrolidone-Thiadiazole molecular structure, which shows potent antibiofilm activity, low cytotoxicity on mammalian cells, no hemolytic activity on healthy human red blood cells, and inhibition of YycG protein autophosphorylation, and indicates that it is a potential inhibitor targetting YycG of bacterial twocomponent system (TCS).…”