engleski

inhibition of quorum sensing with novel chloroquine fumardiamides

Most microbial pathogens exploit adherent growth on various surfaces (i.e., biofilm formation) in order to avoid the effect of antibiotics and host immune cells. A cell-to-cell communication, termed quorum sensing (QS), plays a key role in coordinating the biofilm formation and various other pathogenic pathways. By utilizing QS, microbial cells can detect and respond to cell population density via the production and release of a chemical signal molecule called autoinducer. It is considered that molecules or compounds able to interrupt QS pose less selective pressure on the microbes than the conventional antibiotics, thus, contributing less to antibiotic resistance. Strategies that interrupt the QS-communication outside the cell, also called quorum quenching (QQ), are highly promising since the communication system can be blocked without entering the cell. Therefore, search for novel anti-QS compounds preventing the development of specific group behavior and causing chemical attenuation of biofilm formation is considered the method of choice to combat biofilm infections without boosting the resistance. Quinoline derivatives were shown as effective antagonists of PqsR, the receptor of pqs system of the human pathogen Pseudomonas aeruginosa, which controls the expression of various virulence factors and is involved in the biofilm formation. We report here the synthesis and activity of four novel fumardiamides with chloroquine (CQ) moiety on one side and scaffolds bearing primary or secondary amino groups on the opposite side of the molecule. The C. violaceum ATCC31532 and CV026 strains were used as QS reporters for testing anti-QS and bactericidal activities. Our results revealed that compounds 27, 29 and 30 inhibited QS by approx. 46 %, which is similar to the activity of quercetin, the positive control for QS (56 %). The cell viability staining indicated the tested compounds showed a negligible bactericidal effect in both strains ranging from 6.5to 16.2 %. Since the compounds had no bactericidal effect on the C. violaceum cells, we considered them as new QQs able to block QS without inducing natural selection pressure as traditional antimicrobial agents. Our results could help in further design of agents targeting cell-to-cell communication and may open new avenues for the combat against drug-resistant bacteria.

quinoline derivatives ; chloroquine ; fumardiamide ; quorum sensing inhibition ; quorum quenching

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