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

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.