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.
Highlights
Exploring new directions to combat bacterial infections has become critically important with the rising incidence of hospital-acquired bacterial infections and the global prevalence of bacterial resistance
In line with our continuing efforts to develop new quorum sensing (QS) inhibitors, we explored the potential use of mucochloric acid 7 and mucobromic acid 8 as precursors that could provide access to functionalized lactams [14]
In order to generate a diverse array of lactam analogues, various amines were selected including aliphatic, arylated and heterocyclic amines
Summary
Exploring new directions to combat bacterial infections has become critically important with the rising incidence of hospital-acquired bacterial infections and the global prevalence of bacterial resistance. Traditional antibiotics are either bactericidal (kill bacteria) or bacteriostatic (inhibit the growth of bacteria) [1]. The selective evolutionary pressures exerted by these antibiotics on microorganisms have resulted in the rise and spread of antibiotic resistance [2]. Other factors that have contributed to increased drug resistance include the expanded use of medical devices, treatments for infections in immune-compromised patients and the overuse or mishandling of antibiotics either intentionally or inadvertently [2]. Novel therapeutic approaches to combat bacterial infection and resistance are required [3].
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