Quorum sensing inhibitors: a bargain of effects

Abstract

Many opportunistic pathogenic bacteria rely on quorum sensing (QS) circuits as central regulators of virulence expression. In Pseudomonas aeruginosa, QS-regulated gene expression contributes to the formation and maintenance of biofilms and their tolerance to conventional antimicrobials and the host innate immune system. Therefore, QS is an obvious target for a novel class of antimicrobial drugs which would function to efficiently block reception of the cognate QS signals in vivo, and thereby be capable of inducing chemical attenuation of pathogens. As QS is not directly involved in processes essential for growth of the bacteria, inhibition of QS does not impose harsh selective pressure for development of resistance as with antibiotics. Numerous chemical libraries of both natural and synthetic origin have been screened and several QS-inhibitory compounds have been identified. In animal pulmonary infection models, such inhibitors have proven able to significantly improve clearing of the infecting bacteria and reduce mortality. In addition, several enzymes that are able to inactivate the bacterial QS signal molecules have been identified. This inactivation leads to blockage of QS-mediated virulence of plant pathogens in several models. Quorum sensingBacteria are social organisms capable of interacting with each other and their surroundings. Particularly well described is the ability to coordinate gene expression in accordance with population density, a process termed quorum sensing (QS) (Fuqua et al., 1994). In Gram-negative bacteria this is achieved by production and reception of diffusible signal molecules in the form of acylhomoserine lactones (AHLs) (Fig. 1). The signal molecules are produced by an AHL synthase encoded by homologues of the AHL synthase gene luxI, which was first identified in Vibrio fischeri (Engebrecht & Silverman, 1984). At low population densities, luxI is constitutively expressed at a low, basal level. Hence, the AHLs accumulate in the surroundings. The LuxR family of receptor/response regulator proteins perceives the AHLs. At a certain threshold concentration of AHL, the signal molecule forms a complex with the receptor protein, which becomes activated. The activated receptor-signal complex in turn forms dimers or multimers with other activated LuxR-AHL complexes. These dimers or multimers function as transcriptional regulators controlling expression of QS-regulated target genes. The QS paradigm states that transcription of QS target genes is activated at a certain population density (which is proportional to the AHL concentration) known as the 'quorum size' -the number of bacteria required to activate the QS system (Eberl, 1999;Fuqua et al., 1994;Salmond et al., 1995;Parsek et al., 1999). In Pseudomonas aeruginosa, however, recent research has shown that each individual QS-regulated gene possesses its own specific quorum size. There is not a single population density at which all QS genes are activated; rather, different genes are activated at different population densities Wagner et al....

Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

“…QS has been studied extensively as an obvious target to alleviate bacterial virulence (37). Such approaches have been considered to be advantageous because targeting QS may not impose selective pressure for the development of resistance as we have witnessed with antibiotics.…”

The rhizosphere: a playground and battlefield for soilborne pathogens and beneficial microorganisms

“…Conversely, soilborne plant pathogens can utilize similar strategies to interfere with quorum-regulated antibiotic biosynthesis as a defense strategy against microbial antagonism. Several strategies of quorum sensing inhibition, also refered to as quorum quenching, have been unraveled in the past decade and include repression or blockage of the production of signal molecules, inactivation of the signal molecules or interference with signal perception (reviewed in Zhang and Dong 2004;Rasmussen and Givskov 2006). To date, two types of enzymes that inactivate AHLs have been identified in a range of bacterial species and genera; these include the AHL-lactonases that hydrolyse the lactone ring to yield acyl homoserines with reduced biological activity, and the AHL-acylases that break the amide linkage of AHLs resulting in homoserine lactone and fatty acids, which do not exhibit biological activity (reviewed in Zhang and Dong 2004;Uroz et al 2007).…”

Frontier studies on highly selective bio-regulators useful for environmentally benign agricultural production

“…62) Therefore, QS modulators have potential uses in agrochemical fields by preventing microbial infection in hosts. 63) A compound that specifically regulates QS has been sought in medical and agrochemical pharmacology because it could prevent pathogenicity without killing bacteria, 64) thereby avoiding the emergence of drugresistant strains. Therefore, we screened fungal strains isolated from soil for agonists or antagonists of AHLs using the biosensor Agrobacterium tumefaciens NTL4.…”