Design and Synthesis of Lactams Derived from Mucochloric and Mucobromic Acids as Pseudomonas aeruginosa Quorum Sensing Inhibitors

Abstract

Bacterial infections, particularly hospital-acquired infections caused by Pseudomonas aeruginosa, have become a global threat with a high mortality rate. Gram-negative bacteria including P. aeruginosa employ N-acyl homoserine lactones (AHLs) as chemical signals to regulate the expression of pathogenic phenotypes through a mechanism called quorum sensing (QS). Recently, strategies targeting bacterial behaviour or QS have received great attention due to their ability to disarm rather than kill pathogenic bacteria, which lowers the evolutionary burden on bacteria and the risk of resistance development. In the present study, we report the design and synthesis of N-alkyl- and N-aryl 3,4 dichloro- and 3,4-dibromopyrrole-2-one derivatives through the reductive amination of mucochloric and mucobromic acid with aliphatic and aromatic amines. The quorum sensing inhibition (QSI) activity of the synthesized compounds was determined against a P. aeruginosa MH602 reporter strain. The phenolic compounds exhibited the best activity with 80% and 75% QSI at 250 µM and were comparable in activity to the positive control compound Fu-30. Computational docking studies performed using the LasR receptor protein of P. aeruginosa suggested the importance of hydrogen bonding and hydrophobic interactions for QSI.

Investigating the Mechanism of Action of Diketopiperazines Inhibitors of the Burkholderia cenocepacia Quorum Sensing Synthase CepI: A Site-Directed Mutagenesis Study

“…Quorum sensing inhibitors appear as very promising potentiators of the classical antibiotic therapy to treat dangerous infections such as those caused by B. cenocepacia , for which a lack of new solutions is massively reported ( Horsley et al, 2011 ; Regan and Bhatt, 2016 ; Scoffone et al, 2017 ). Searching in PubMed for “quorum sensing inhibitors” retrieves 51 results in the first 5 months of 2018, which shows the increasing interest in alternative routes to counteract the emergence of resistance among bacteria such as Proteus mirabilis ( Yu et al, 2018 ), Salmonella ( de Almeida et al, 2018 ), Pseudomonas aeruginosa ( Almohaywi et al, 2018 ), Staphylococcus aureus ( Karathanasi et al, 2018 ).…”

Potassium 2-methoxy-4-vinylphenolate: a novel hit exhibiting quorum-sensing inhibition inPseudomonas aeruginosa viaLasIR/RhlIR circuitry

“…[21][22][23][24] Literature is full of reports particularly on quorum sensing inhibition in Pseudomonas aeruginosa. [25][26][27][28][29][30][31][32][33][34][35][36] Carvacrol (essential oil) was reported to inhibit biolm formation in S. aureus and P. aeruginosa and pyocyanin production in P. aeruginosa signicantly. 37 Baicalein (avonoid from the roots of Scutellaria baicalensis) was demonstrated to inhibit several virulence factors and biolm formation.…”

Halogen-Furan-2(5H)-One Derivatives Decrease Biofilm Production in Pseudomonas aeruginosa.

“…These results suggest that B2 and B6 inhibited the rhamnolipids production and biofilm formation by a mechanism independent of QS. Even though mucobromic acid (A1) has been used to obtain compounds with anti-QSS activity, as far as we know, this is the first time that A1 has been evaluated as an inhibitor of the quorum-sensing system [21,22]…”