Computer-Aided Design of Agents That Inhibit the cep Quorum-Sensing System of Burkholderia cenocepacia

Abstract

Recent research has provided evidence that interference with bacterial cell-to-cell signaling is a promising strategy for the development of novel antimicrobial agents. Here we report on the computer-aided design of novel compounds that specifically inhibit an N-acyl-homoserine lactone-dependent communication system that is widespread among members of the genus Burkholderia. This genus comprises more than 30 species, many of which are important pathogens of animals and humans. Over the past few years, several Burkholderia species, most notably Burkholderia cenocepacia, have emerged as important opportunistic pathogens causing severe pulmonary deterioration in persons with cystic fibrosis. As efficient treatment of Burkholderia infections is hampered by the inherent resistance of the organisms to a large range of antibiotics, novel strategies for battling these pathogens need to be developed. Here we show that compounds targeting the B. cenocepacia signaling system efficiently inhibit the expression of virulence factors and attenuate the pathogenicity of the organism.The gram-negative bacterium Burkholderia cepacia was first described as a phytopathogen associated with a soft rot of onion bulbs (2). Taxonomic studies of the past few years have shown that B. cepacia-like organisms comprise a group of closely related strains, collectively referred to as the B. cepacia complex. Strains of the B. cepacia complex are ubiquitously distributed in nature and have been isolated from soil, water, plants, and industrial settings. Over the past few years, B. cepacia complex strains have also emerged as opportunistic pathogens of humans (3,5,16,26). These strains can cause life-threatening lung infections in patients requiring mechanical ventilation and in individuals with chronic granulomatous disease or cystic fibrosis (CF). The clinical outcome of infection with B. cepacia complex in CF patients is varied and unpredictable, ranging from asymptomatic carriage to a fulminant and fatal pneumonia, the so-called cepacia syndrome (10). Although all nine B. cepacia genomovars (Gv.) described to date have been isolated from CF patients, Burkholderia multivorans (Gv. II) and Burkholderia cenocepacia (Gv. III) are most commonly found in clinical samples (18). A major problem with Burkholderia infections is the intrinsic resistance of the organism to various antibiotics and biocides, impeding effective medical treatment.B. cenocepacia utilizes an N-acyl homoserine lactone (AHL)-dependent quorum-sensing (QS) system to express certain genes in a cell density-dependent manner. This regulatory system consists of the AHL synthase CepI, which directs the synthesis of the signal molecule N-octanoylhomoserine lactone (C8-HSL) and the transcriptional regulator CepR (4,14). When the concentration of C8-HSL reaches a critical threshold concentration, the signal molecule binds to the cognate receptor protein CepR, which in turn leads to the induction or repression of target genes. The cep system was shown to positively regulate the expression of...

Design, synthesis, biological evaluation and toxicity studies of N,N-disubstituted biguanides as quorum sensing inhibitors

“…However, a number of reports of identification of structurally distinct non-AHL analogous molecules as QS inhibitors (Müh et al, 2006;Sabbah et al, 2012;Riedel et al, 2006;Park et al, 2006;Degrassi et al, 2002;Jadhav et al, 2011) which bind with the receptor in a non-competitive fashion and thus retards QS signalling. These categories include inhibitors carrying non-AHL core of tetrazole (Müh et al, 2006), thiophene (Riedel et al, 2006), cyclic dipeptides (2,5 diketopiperazines) (Park et al, 2006;Degrassi et al, 2002), novel triphenyl scaffold (Campbell et al, 2009) and some small molecules with electrophilic functionalities (isothiocyanates, haloacetamides, etc.)…”

“…These categories include inhibitors carrying non-AHL core of tetrazole (Müh et al, 2006), thiophene (Riedel et al, 2006), cyclic dipeptides (2,5 diketopiperazines) (Park et al, 2006;Degrassi et al, 2002), novel triphenyl scaffold (Campbell et al, 2009) and some small molecules with electrophilic functionalities (isothiocyanates, haloacetamides, etc.) (Amara et al, 2009).…”

Inhibition of Quorum Sensing in Serratia marcescens AS-1 by Synthetic Analogs of N -Acylhomoserine Lactone

“…Synthetic compounds modeled on the natural AHLs were evaluated for both their inducing activity and their ability to competitively inhibit the action of AHL in Vibrio fischeri, Burkholderia cenocepacia, and Pseudomonas aeruginosa (1,3,13,22,24,28,29). Halogenated furanones, produced by the red alga Delisea pulchra, inhibit quorum sensing in a number of bacteria (4,5,9,20,21).…”

Interfering with “Bacterial Gossip”

“…This indicated that these furanone derivatives are highly toxic to the bacteria since genetic analysis shows that a functional QS system is not required for biofilm formation in vitro. Since the discovery of the halo-furanones, a number of papers have reported on synthesis of QSI compounds by means of organic chemistry approach (Borlee et al 2008;Geske et al 2007Geske et al , 2008aMattmann et al 2008;Muh et al 2006;Olsen et al 2002;Persson et al 2005a, b;Riedel et al 2006). However, a detailed overview of this is not the scope of this chapter.…”