Design, Synthesis, and Biological Evaluation of Indole Derivatives Targeting LsrK as AI‑2 Quorum Sensing Inhibitors

A series of novel indole derivatives targeting LsrK as
AI-2 quorum
sensing (QS) inhibitors against antimicrobial resistance (AMR) were
designed, synthesized, and evaluated in vitro and in vivo. 3-Cyano-indol
derivative A19 showed more potent activity than that
of all reported LsrK inhibitors, with an IC50 value of
340 nM and a KD value of 485 nM. The in-depth
biological evaluation indicated that the potent compounds A19, A40, and A49 inhibited biofilm formation
and bacterial motility and changed biofilm morphology through AI-2
QS inhibition rather than direct antibacterial effects. Surprisingly,
they showed the synergistic eradication effect for preformed biofilms
combined with antibiotics and no obvious in vitro hemolysis and cellular
toxicity. Moreover, the best-performing compound A40 showed
favorable oral PK properties. In summary, this work identified that A40 was a promising lead with a novel scaffold for the further
development of LsrK inhibitors as AI-2 QS inhibitors against AMR.