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 and make 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.
Highlights
Quorum sensing (QS) is a well-known cell-to-cell communication in microorganisms [1], through which bacteria regulate cell density-dependent behavior, such as secreting virulence factors, motility, and biofilm formation, aids bacteria in infections and drug resistance [2]
Which is the maximum treated concentration, cyclic dipeptides (CDPs) suppressed the production of pyocyanin obviously, but did not affect the bacterial growth, especially for c(WE), c(WT), c(wS), c(Ws), and c(ws), which remarkably reduced the yield of pyocyanin by 75%, 70%, 89%, 81%, and 86%, respectively
As one kind of stable secondary metabolites, numerous cyclic dipeptides were discovered from microorganisms and demonstrated as inhibitors, including antitumor, antiviral, and antibacterial [26,27]
Summary
Quorum sensing (QS) is a well-known cell-to-cell communication in microorganisms [1], through which bacteria regulate cell density-dependent behavior, such as secreting virulence factors, motility, and biofilm formation, aids bacteria in infections and drug resistance [2]. Which is the maximum treated concentration, CDPs suppressed the production of pyocyanin obviously, but did not affect the bacterial growth, especially for c(WE), c(WT), c(wS), c(Ws), and c(ws), which remarkably reduced the yield of pyocyanin by 75%, 70%, 89%, 81%, and 86%, respectively Elastase activity, another important virulence factor regulated by the QS system of P. aeruginosa, was assessed using elastin-Gongo red. A. eareurguignionsoasaPAPOA1O1 TThhee bbiioofifillmmffoorrmmaatitoionnofoPf.Pae.rauegriungoisnao, swa,hwichhiwchaswalaws aaylws caoynssicdoenrseiddteorebde QtoS-breegQuSla-treedg,uliastecdom, isplceoxmapnldexasasnodciaatsesdocwiaittehdmwanityh pmearsniystepnetrsinisfteecntitoinnsfeacntidoninscarenadseindcarneatisbeidotaicnrteibsiiso-tic rteasnisctea.ncAel.lAtellstteedsteCdDCPDs Pexsheixbhitiebditeadntai-nbtiio-bfiilomfilamctaivcittiyvitaygaaignasitnPs.t Pae.rauegriungoisnaoPsaAPOA1Oin ian a ddoossee--ddeeppeennddeenntt mmaannnneerr((FFiigguurreeSS44).).TThheecc(W(WSS) )aanndditistsisiosommeresr,sc,(cw(wS)Sa)nadndc(Wc(Ws),si)n, hinibhiitbeidted tthheebbiiooffiillmm ffoorrmmaattiioonn bbyy 5533%%,, 5544%%,,aanndd5566%%,,rreessppeecctitviveelyl,yd, disipslpalyaiynigngmmoroereeffiefcfiiecniecnyctyhathnan other cyclic dipeptides, at a concentration of 1 mM (Figure 5a) These CDPs decreased the mature biofilm by 40–56% (Figure 5b), showing a similar ability in anti-biofilm formation. FFiigguurree 77.. ((aa)) HHeemmoollyyssiiss ooff sshheeeepp rreedd bblloooodd cceellllss iinn tthhee pprreesseenncceeooffCCDDPPssoovveerraabbrrooaaddrraannggeeooff ccoonncceennttrraattiioonnss ((00..11−−1100mmMM).).CCyytotototoxxicicitiytyoof fCCDDPPsstotoNNIHIH33TT33cceelllsls(b(b))aannddAA554499cceelllsls((cc))..PPeerrcceenntt ccyyttoottooxxiicciittyy rreellaattiivveettooccoonntrtorolslsisisrerperperseesnetnetdedasams emanea±nst±ansdtaarnddadredvidateivoinatoifotnhroefetbhiroeleogbiicoallorgeipca- l rleicpaltiecsa.tes
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