Abstract
The increasing common occurrence of antibiotic-resistant bacteria has become an urgent public health issue. There are currently some infections without any effective treatment, which require new therapeutic strategies. An attractive alternative is the design of compounds capable of disrupting bacterial communication known as quorum sensing (QS). In Gram-negative bacteria, such communication is regulated by acyl-homoserine lactones (AHLs). Triggering of QS after bacteria have reached a high cell density allows them to proliferate before expressing virulence factors. Our group previously reported that hexyloxy phenylimidazoline (9) demonstrated 71% inhibitory activity of QS at 100 μM (IC50 = 90.9 μM) in Chromobacterium violaceum, a Gram-negative bacterium. The aim of the present study was to take 9 as a lead compound to design and synthesize three 2-imidazolines (13–15) and three 2-oxazolines (16–18), to be evaluated as quorum-sensing inhibitors on C. violaceum CV026. We were looking for compounds with a higher affinity towards the Cvi receptor of this bacterium and the ability to inhibit QS. The binding mode of the test compounds on the Cvi receptor was explored with docking studies and molecular dynamics. It was found that 8-pentyloxyphenyl-2-imidazoline (13) reduced the production of violacein (IC50 = 56.38 μM) without affecting bacterial growth, suggesting inhibition of quorum sensing. Indeed, compound 13 is apparently one of the best QS inhibitors known to date. Molecular docking revealed the affinity of compound 13 for the orthosteric site of N-hexanoyl homoserine lactone (C6-AHL) on the CviR protein. Ten amino acid residues in the active binding site of C6-AHL in the Cvi receptor interacted with 13, and 7 of these are the same as those interacting with AHL. Contrarily, 8-octyloxyphenyl-2-imidazoline (14), 8-decyloxyphenyl-2-imidazoline (15), and 9-decyloxyphenyl-2-oxazoline (18) bound only to an allosteric site and thus did not compete with C6-AHL for the orthosteric site.
Highlights
Academic Editor: Oliver Sutcliffe e increasing common occurrence of antibiotic-resistant bacteria has become an urgent public health issue. ere are currently some infections without any effective treatment, which require new therapeutic strategies
We were looking for compounds with a higher affinity towards the Cvi receptor of this bacterium and the ability to inhibit quorum sensing (QS). e binding mode of the test compounds on the Cvi receptor was explored with docking studies and molecular dynamics
Various analogs and bioisosteres of acyl-homoserine lactones (AHLs) have been synthesized as inhibitors of Gram-negative bacteria [12], and some of them designed to interfere with QS in Chromobacterium violaceum [14]
Summary
Academic Editor: Oliver Sutcliffe e increasing common occurrence of antibiotic-resistant bacteria has become an urgent public health issue. ere are currently some infections without any effective treatment, which require new therapeutic strategies. In Gram-negative bacteria, such communication is regulated by acyl-homoserine lactones (AHLs). 1. Introduction e quorum sensing (QS) is a mechanism of bacterial communication involved in regulating the expression of genes linked to the production of virulence factors, among other functions. Introduction e quorum sensing (QS) is a mechanism of bacterial communication involved in regulating the expression of genes linked to the production of virulence factors, among other functions Such virulence factors include lytic enzymes, proteases, siderophores, and adhesins [1,2,3]. Various analogs and bioisosteres of AHLs have been synthesized as inhibitors of Gram-negative bacteria [12], and some of them designed to interfere with QS in Chromobacterium violaceum [14]. Chromobacterium violaceum is a Gram-negative bacterium whose autoinducer is hexanoyl homoserine lactone (C6-AHL, 1). C. violaceum was used as a biosensor [15]
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