Indole-based novel small molecules for the modulation of bacterial signalling pathways

Abstract

Gram-negative bacteria such as Pseudomonas aeruginosa use N-acylated L-homoserine lactones (AHLs) as autoinducers (AIs) for quorum sensing (QS), a major regulatory and cell-to-cell communication system for social adaptation, virulence factor production, biofilm formation and antibiotic resistance. Some bacteria use indole moieties for intercellular signaling and as regulators of various bacterial phenotypes important for evading the innate host immune response and antimicrobial resistance. A range of natural and synthetic indole derivatives have been found to act as inhibitors of QS-dependent bacterial phenotypes, complementing the bactericidal ability of traditional antibiotics. In this work, various indole-based AHL mimics were designed and synthesized via the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and N,N'-dicyclohexylcarbodiimide (DCC) mediated coupling reactions of a variety of substituted or unsubstituted aminoindoles with different alkanoic acids. All synthesized compounds were tested for QS inhibition using a P. aeruginosa QS reporter strain by measuring the amount of green fluorescent protein (GFP) production. Docking studies were performed to examine their potential to bind and therefore inhibit the target QS receptor protein. The most potent compounds 11a, 11d and 16a showed 44 to 65% inhibition of QS activity at 250 μM concentration, and represent promising drug leads for the further development of anti-QS antimicrobial compounds.

A genomic and transcriptomic approach to investigate the blue pigment phenotype in Pseudomonas fluorescens

“…This result does not agree with the findings by Caputo et al (2015); the considerably higher value of the molecule confirms the previous hypothesis that it is plausible that an indigo-derivative is formed by colored P. fluorescens strains. Recently, a study reported the involvement of indigo-derivative molecules as modulators in bacterial signaling pathways (Biswas et al, 2015). This result suggests a potential function for the blue pigment.…”

Roles of Indole as an Interspecies and Interkingdom Signaling Molecule

“…For example, indole-derived flustramine and pyrroloindoline triazole amides inhibited biofilm formation by Acinetobacter baumannii, E. coli, and methicillin-resistant S. aureus more efficiently than did indole [46,67] and 2-aminobenzimidazole inhibited biofilm formation by P. aeruginosa [68]. In another study, the brominated furanone motif and indole were combined to produce desformylflustrabromine, which inhibited biofilm formation by S. aureus and E. coli [45], and the N-acylated L-homoserine lactone motif and indole were combined to inhibit P. aeruginosa QS [69]. Recently, two review papers described indole-containing small molecules that modulate bacterial behaviors and the synthetic approaches they used [29,30].…”

New Approaches for Competing Microbial Resistance and Virulence

“…Other furanone analogs have been developed including S-phenyl-l-cysteine sulfoxide and diphenyl disulfide [66] and tetrazole derivatives [67]. Furthermore, synthetic LasR derivatives have been developed such as indole derivatives, non-AHL-like antagonists [68], the synthesized azines derivatives, 4-(alkyloxy)-6-methyl-2H-pyran-2-one [69] and aspirin [70]. Triphenyl hybridγ-butyrolactones and cyclopentanones derivatives are potent inhibitors of LuxR [71].…”