Quorum Sensing Inhibition by Phenothiazines and Related Compounds

Zoltan      Gabor Varga; Mira      Agnes Szabo; Zsuzsanna      Schelz; Erno      Szegedi; Leonard      Amaral; Jozsef      Molnar

Abstract

A quorum is the smallest number of people able to organize the decisions concerning functional activity. Similarly microbes use chemical signal molecules to make population size-dependent “decisions” by changing their gene regulations.

The inhibition of quorum sensing (QS) by phenothiazines and structurally related molecules, e.g. amitriptyline, promethazine, acridine orange, imipramine, promazine, diethazine, desipramine, desertomycin and 5-fluorouracil as positive control was studied with Chromobacterium violaceum 026 as a sensor strain, which detects short carbon chain AHLs by the development of a purple pigment. The AHL was produced by Novospingobium Ezf 10-17, and the antibiotic-resistant clinical isolates, E. coli 31298.

The QS was demonstrated as a signal transmission between the two bacterial strains. The most effective inhibitors of QS were amitriptyline, promethazine, acridine orange and desertomycin. Imipramine and diethazine were moderately active, while chlorprothixene was ineffective relative to 5-fluorouracil as positive control. The direct complex formation between AHL and QS inhibitors markedly reduced the QS in a chromogenic test. The AHL-neutralizing effect of the related compounds was shown by chromogenic method.

The inhibition of QS signal transmission appears to be related to the quasi-planar structure and electron donor capacity of the conjugated π-electron system of the tricyclic framework. The results can be exploited in rational drug design as a new way to reduce the QS mediated processes eg. virulence of pathogens, to vary the formation of biofilms and to modify antibiotic resistance.

Keywords: 5-Fluorouracil, Amitriptyline, Homoserine lactone complexes, Imipramine, Promethazine, Quorum quenching, quorum, quorum sensing, phenothiazines, acridine orange, diethazine, desipramine, desertomycin, Chromobacterium violaceum, E. coli, Homoserine, lactone complexes, N-acyl homoserine lactones, tricyclic compounds, C. violaceum, plasmid