Effects of hydroxyl group in cyclo(Pro-Tyr)-like cyclic dipeptides on their anti-QS activity and self-assembly.

We investigated the influence of hydroxyl groups on the anti-quorum-sensing (anti-QS) and anti-biofilm activity of structurally similar cyclic dipeptides, namely cyclo(-Pro--Tyr), cyclo(-Hyp--Tyr), and cyclo(-Pro--Phe), against PAO1. Cyclo(-Pro--Phe), lacking hydroxyl groups, displayed higher virulence factor inhibition and cytotoxicity, but showed less inhibitory ability in biofilm formation. Cyclo(-Pro--Tyr) and cyclo(-Hyp--Tyr) suppressed genes in both the and systems, whereas cyclo(-Pro--Phe) mainly downregulated I and R expression. These cyclic dipeptides interacted with the QS-related protein LasR, with similar binding efficiency to the autoinducer 3OC12-HSL, except for cyclo(-Pro--Phe) which had lower affinity. In addition, the introduction of hydroxyl groups significantly improved the self-assembly ability of these peptides. Both cyclo(-Pro--Tyr) and cyclo(-Hyp--Tyr) formed assembly particles at the highest tested concentration. The findings revealed the structure-function relationship of this kind of cyclic dipeptides and provided basis for our follow-up research in the design and modification of anti-QS compounds.