Anti-Quorum-Sensing Activity of Tryptophan-Containing Cyclic Dipeptides

Abstract

Quorum sensing (QS) can regulate the pathogenicity of bacteria and the production of some virulence factors. It is a promising target for screening to find anti-virulence agents in the coming post-antibiotics era. Cyclo (L-Trp-L-Ser), one variety of cyclic dipeptides (CDPs), isolated from a marine bacterium Rheinheimera aquimaris, exhibited anti-QS activity against Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PAO1. Unlike the CDPs composed of phenylalanine or tyrosine, the anti-QS activity has been widely studied; however, Cyclo (L-Trp-L-Ser) and derivatives, containing one tryptophan unit and one non-aromatic amino acid, have not been systematically explored. Herein, the cyclo (L-Trp-L-Ser) and seven derivatives were synthesized and evaluated. All tryptophane-contained CDPs were able to decrease the production of violacein in C. violaceum CV026 and predicted as binding within the same pocket of receptor protein CviR, but in lower binding energy compared with the natural ligand C6HSL. As for P. aeruginosa PAO1, owning more complicated QS systems, these CDPs also exhibited inhibitory effects on pyocyanin production, swimming motility, biofilm formation, and adhesion. These investigations suggested a promising way to keep the tryptophan untouched but made modifications on the non-aromatic unit to increase the anti-QS activity and decrease the cytotoxicity, thus developing a novel CDP-based anti-virulence agent.

Uncovering Untapped Carboxylic Acid Reductases (CARs) for One-Step Biosynthesis and Diversification of Bioactive Nitrogen-Containing Heterocycles

“…These compounds showed QS inhibition with IC 50 values of 26.8, 7.9, 30.7, and 56.2 μM, respectively (Figure S9). Interestingly, our findings suggest that pyrazines with a benzyl substitute have stronger inhibitory effects on QS than their previously reported analog cyclodipeptides (CDPs). − Molecular docking (Figure S10) indicated that these compounds might compete with QS molecules for binding to the QS receptor CviR (PDB 3QP8), implying their potential to combat other strains that use N-Acyl homoserine lactone (AHL) as their signaling molecule, such as Vibrio and Pseudomonas . Given the protease inhibition potential demonstrated by amino acid–based N-heterocycles, including calpain inhibitors PZN-FV and PZN-YL, , as well as SARS-CoV-2 inhibitor PZ-WW, we next sought to investigate the protease inhibitory activities of isolated compounds.…”

“…In order to demonstrate the potential of our library, we conducted a proof-of-principle study by screening the mixture for potential QS inhibitors. This was based on our assay of natural products and previous research indicating that N-heterocycles, such as cyclic dipeptides − or pyrrolones, can inhibit QS. Next, we aimed to extend this screening to the chemical library generated by CARs (Figure A).…”

Quorum Quenching Strains Isolated from the Microbiota of Sea Anemones and Holothurians Attenuate Vibriocorallilyticus Virulence Factors and Reduce Mortality in Artemiasalina

“…Curiously, a strain of R. aquimaris capable of interfering with QS systems through the production of a diketopiperazine has been reported [ 75 ]. Recently, it has also been described that synthetic diketopiperazines modified from the natural compound that is present in this species is capable of interfering with QS-related phenotypes in P. aeruginosa [ 76 ].…”

Pseudomonas aeruginosa inhibits quorum-sensing mechanisms of soft rot pathogen Lelliottia amnigena RCE to regulate its virulence factors and biofilm formation

“…Moreover, they also reported that fungi, Alternaria alternate derived Cyclo(Pro-Tyr), have the potential to inhibit the swarming motility of S. liquefaciens . The molecular docking studies showed that DKPs competitively bind to the receptor, CviR in C. violaceum or LasR receptor systems in P. aeruginosa PA01 (Holden et al, 1999 ; Sun et al, 2016 ; Wang et al, 2022 ). The analog binding changes the receptor's confirmation, which cannot bind to the target site.…”