Screening for novel quorum-sensing inhibitors to interfere with the formation of Pseudomonas aeruginosa biofilm

Abstract

The objective of this study was to screen for novel quorum-sensing inhibitors (QSIs) from traditional Chinese medicines (TCMs) that inhibit bacterial biofilm formation. Six of 46 active components found in TCMs were identified as putative QSIs based on molecular docking studies. Of these, three compounds inhibited biofilm formation by Pseudomonas aeruginosa and Stenotrophomonas maltophilia at a concentration of 200 mM. A fourth compound (emodin) significantly inhibited biofilm formation at 20 mM and induced proteolysis of the quorum-sensing signal receptor TraR in Escherichia coli at a concentration of 3-30 mM. Emodin also increased the activity of ampicillin against P. aeruginosa. Therefore, emodin might be suitable for development into an antivirulence and antibacterial agent. INTRODUCTIONPseudomonas aeruginosa, an opportunistic human pathogen, may cause acute infections in hospitalized patients, can be isolated from the environment, particularly from soil and water, and it regularly contaminates medical devices (Stover et al., 2000). It is also the predominant cause of chronic lung infection in cystic fibrosis patients (Frederiksen et al., 1997) and has recently been recognized as one of the main causes of chronic wound infections (Gjødsbøl et al., 2006). P. aeruginosa can infect patients by producing a wide range of virulence factors, the expression levels of which are tightly regulated. Key to this regulation is cell density-dependent cell-to-cell signalling, which is termed quorum sensing (QS) (Rumbaugh et al., 2000). As in many other bacteria, QS controls secretion of virulence factors (Mittal et al., 2006), biofilm formation (Waters et al., 2008) and the exchange of DNA (Fuqua & Winans, 1996) in P. aeruginosa. The biofilm mode of growth is recognized as an important bacterial trait that is relevant to infections (Costerton et al., 1994). Many infections involve the formation of bacterial biofilms, which are bacterial communities that settle and proliferate on surfaces and are covered by exopolymers (Lewis, 2007). Once established, biofilms are difficult to eradicate and become a source of secondary infection (Jones et al., 2009). Moreover, bacteria embedded in biofilms are more tolerant than planktonic cells of antibiotics (Donlan & Costerton, 2002;Drenkard, 2003). The dose of antibiotics needed in this situation will often exceed the highest deliverable dose, which makes efficient treatment impossible.QS, as a regulatory mechanism, enables bacteria to make collective decisions with respect to the expression of a specific set of genes that involve the production, release and subsequent detection of chemical signalling molecules, such as N-acylhomoserine lactones (AHLs) that are commonly used by Gram-negative bacteria. When the concentration of AHLs reaches a certain threshold level, binding to a receptor molecule (for example, LuxR) is promoted and the activated LuxR-AHL complex forms dimers or polymers, which, in turn, act as transcriptional regulators of target genes in the QS regulon (Parsek & Greenbe...

Antibacterial and cytotoxic activities of naphthoquinone pigments from Onosma visianii Clem

“…Previously published data indicated notable activity of shikonin derivatives against gram positive bacteria (and generally low activity against gram negative bacteria), with the fact of remarkable differences of antibacterial potency due to different approaches of measuring MIC values (Papageorgiou et al, 1999[23]; Andujar et al, 2013[3]). On the other hand, some results showed good antibacterial activity against some gram negative species (Brigham et al, 1999[4]; Ding et al, 2011[9]). Our results indicated that isolated naphthoquinone derivatives at the same time showed a good activity towards both gram positive and gram negative bacteria.…”

Antibacterial Flavonoids from Medicinal Plants Covalently Inactivate Type III Protein Secretion Substrates

“…Since many plant bacterial pathogens use type III secretion systems to cause disease and sense flavonoids 30 , it is possible that some of these compounds may have evolved as a consequence host-pathogen interactions. Moreover, flavonoids have also been reported to target other anti-infective properties such as expression of virulence genes 31,32 , toxin activity 33-35 , quorum sensing 36-39 and biofilm formation 40,41 in bacterial pathogens as well as attenuate destructive host inflammation 42-44 . Given the broad pharmacological activities of flavonoids, these plant metabolites may affect microbial virulence mechanisms, including type III protein secretion substrates shown here, in addition to host pathways for their anti-infective properties in vivo .…”

Thromboresistant/anti-biofilm catheters via electrochemically modulated nitric oxide release

“…[5] Indeed, since the extracellular polymeric matrices of biofilms protect bacterial cells, most antibiotic treatments are ineffective. [6] Several strategies, such as modified surfaces [7] , silver particle doped materials [8–9] and anti-quorum sensing drugs [10–11] have been suggested over the last decades to either prevent or exterminate biofilms. Yet, the problem of biofilm formation and concomitant catheter induced infections persists, suggesting that other novel and more effective strategies are needed.…”