Structure–activity Relationships of furanones, Dihydropyrrolones and Thiophenones As Potential Quorum Sensing Inhibitors

Abstract

Since their initial isolation from the marine alga Delisea pulchra, bromofuranones have been investigated as potential inhibitors of quorum sensing (QS) in various bacterial strains. QS is an important mechanism by which bacteria co-ordinate their molecular response to the environment. QS is intrinsically linked to bacterial antibiotic resistance. Inspired by nature, chemists have developed a wide variety of synthetic analogs in an effort to elucidate the structure–activity relationships of these compounds, and to ultimately develop novel antimicrobial agents. In this work, we describe advances in this field while paying particular attention to apparent structure–activity relationships. This review is organized according to the main ring systems under investigation, namely furanones, dihydropyrrolones and thiophenones.

The Role of Quorum Sensing Molecules in Bacterial–Plant Interactions

“…The result of halogenated furanones is the inhibition of biofilm production by bacteria. Although they are QSIs capable of inhibiting the QS systems of many bacteria, they show toxicity to host cells at higher concentrations [ 81 , 82 , 83 ].…”

Quorum sensing in human gut and food microbiomes: Significance and potential for therapeutic targeting

“…It is anticipated that metagenomics and metatranscriptomics will guide studies in this relatively novel area to determine the effect of QSI on microbial communities, whilst genetic engineering can be used to improve and maximise the potential of QQ enzymes derived from natural environments (Billot et al, 2020). Advances in the field of chemistry such as structure-activity studies of synthetic QSM analogues (Rajamani et al, 2008;Lyons et al, 2020) naturally complement such bioprospecting and rational design approaches. Perhaps some of the most exciting research in the field has emerged at the interdisciplinary juncture between biology and engineering occupied by the field of synthetic biology .…”

Design and Synthesis of 4-Fluorophenyl-5-methylene-2(5H)-furanone Derivatives as Potent Quorum Sensing Inhibitors

“…Among them, furanone-30 ( 5 , Figure ) is a well-recognized and effective QSI which not only inhibits the production of extracellular virulence factors and the development of antibiotic-resistant biofilms in a dose-dependent manner but also effectively clears P. aeruginosa in a pulmonary mouse model . Interestingly, compounds 6 , 7 , and 8 (Figure ), with an alkyl chain at the C-3 position, despite being less active than 5 , are more likely to be QSIs due to their low toxicity . Cadiolide analog 9 (Figure ), designed and synthesized by Mairink et al, effectively inhibits the biofilm formation of Gram-positive and Gram-negative bacteria with IC 50 values of 7.5 ± 2.6, 3.6 ± 2.1, and 0.7 ± 0.4 μg/mL against Klebsiella pneumoniae , Enterococcus faecalis , and Staphylococcus aureus , respectively, and shows no or low effect on planktonic growth .…”

“…20 Interestingly, compounds 6, 7, and 8 (Figure 2), with an alkyl chain at the C-3 position, despite being less active than 5, are more likely to be QSIs due to their low toxicity. 21 Cadiolide analog 9 (Figure 2), designed and synthesized by Mairink et al, effectively inhibits the biofilm formation of Gram-positive and Gram-negative bacteria with IC 50 values of 7.5 ± 2.6, 3.6 ± 2.1, and 0.7 ± 0.4 μg/mL against Klebsiella pneumoniae, Enterococcus faecalis, and Staphylococcus aureus, respectively, and shows no or low effect on planktonic growth. 22 Our laboratory has tried to design and synthesize aryl-substituted pyrrolidone derivatives and evaluate their QS inhibitory activities.…”