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Current treatments for Pseudomonas aeruginosa infections are becoming less effective because of the increasing rates of multi-antibiotic resistance. Pharmacological targeting of virulence through inhibition of quorum sensing (QS) dependent virulence gene regulation has considerable therapeutic potential. In P. aeruginosa, the pqs QS system regulate...
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The opportunistic pathogen Pseudomonas aeruginosa employs quorum sensing to govern the production of many virulence factors. Interference with quorum sensing signaling has therefore been put forward as an attractive approach to disarm this pathogen. Here, we analyzed the quorum quenching properties of natural and engineered (2-alkyl-)3-hydroxy-4(1H...
Citations
... [22][23][24][25][26][27] In this context, a potentially effective and sustainable approach involves using smallmolecule synthetic inhibitors or antagonists to disrupt the signalling cascade. [28][29][30][31][32][33][34][35][36] In principle, antagonists could be designed to specifically target the signaling pathways involved in virulence, providing a more targeted approach compared to the chemical degradation of signaling molecules with broad-spectrum treatments, such as KMnO4 in our previous study. 18 However, while several inhibitors of N-acylated L-homoserine lactones (AHLs) 37 -the most common signal class in gram-negative bacteriahave been reported, [38][39][40][41] inhibitors of less common signaling molecule classes remain understudied. ...
The bacterial plant pathogen Pseudomonas syringae causes significant damage to economically important crops worldwide. These bacteria coordinate their behavior and virulence through specific signaling compounds, such as the diazeniumdiolate leudiazen. Conventional antibacterial treatments enable the development of resistant strains. A more attractive treatment strategy would involve antagonists that suppress the expression of virulence factors without killing the pathogen, potentially reducing the risk of resistance development. Herein, we present the design and synthesis of analogs of leudiazen, which positively regulates the production of mangotoxin in P. syringae pv. syringae (Pss). Several compounds display inhibitory activity towards mangotoxin production, and a lead compound abolishes necrosis in infected tomato leaves, without significantly affecting bacterial growth. Thus, this study represents a promising advance towards developing effective and sustainable methods for bacterial disease control.
... To address this, we recently reported a high throughput chemical and in silico screening of inhibitors for the pqs system, resulting in the discovery of several potent quorum sensing inhibitors (QSIs) that could alleviate recalcitrant infections caused by P. aeruginosa when administered in combination with the antibiotic ciprofloxacin (CIP). 10,13,14 Particularly high potency was observed for (R)-2-(4-(3-(6-chloro-4-oxoquinazolin-3(4H)-yl)-2-hydroxypropoxy)phenyl)acetonitrile (QSI61), (hit compound 61 within the screen 10 ) however its in vitro anti-biofilm activity was hindered by the poor penetration of the molecule through the thick exopolymeric matrix. ...
Antimicrobial resistance is a threat to public health for which new treatments are urgently required. The capability of bacteria to form biofilms is of particular concern as it enables high bacterial tolerance to conventional therapies by reducing drug diffusion through the dense, exopolymeric biofilm matrix and the upregulation of antimicrobial resistance machinery. Quorum sensing (QS), a process where bacteria use diffusible chemical signals to coordinate group behaviour, has been shown to be closely interconnected with biofilm formation and bacterial virulence in many top priority pathogens including Pseudomonas aeruginosa. Inhibition of QS pathways therefore pose an attractive target for new therapeutics. We have recently reported a new series of pqs quorum sensing inhibitors (QSIs) that serve as potentiators for antibiotics in P. aeruginosa infections. The impact on biofilms of some reported QSIs was however hindered by their poor penetration through the bacterial biofilm, limiting the potential for clinical translation. In this study we developed a series of poly(β-amino ester) (PBAE) triblock copolymers and evaluated their ability to form micelles, encapsulate a QSI and enhance subsequent delivery to P. aeruginosa biofilms. We observed that the QSI could be released from polymer micelles, perturbing the pqs pathway in planktonic P. aeruginosa. In addition, one of the prepared polymer variants increased the QSIs efficacy, leading to an enhanced potentiation of ciprofloxacin (CIP) action and therefore improved reduction in biofilm viability, compared to the non-encapsulated QSI. Thus, we demonstrate QSI encapsulation in polymeric particles can enhance its efficacy through improved biofilm penetration.
... The main research contents include: structure, function, regulation and inhibition mechanism of receptors of different types of QS signal molecules, as well as their relationship with bacterial virulence and biofilm. P. aeruginosa, signal pathway, and anti-infection are frequently occurring concepts in this cluster (Soukarieh et al., 2020;Schutz et al., 2021;Soukarieh et al., 2021;Boopathi et al., 2022;Hamed et al., 2023). The time line visualization can help us further understand the changes of research interests over time and identify the most active research directions at present. Figure 6 shows active periods of 17 clusters with most co-citations identified by co-cited analysis. ...
... Although it has few nodes and small areas, it may continue to grow and expand，and may become a future research hotspot. #7 pseudomonas aeruginosa(2009Ali et al., 2017;Bzdrenga et al., 2017 Bzdrenga et al., ), and #5 pqsr (2012 Bzdrenga et al., - 2020 (Lee and Zhang, 2015;Dickey et al., 2017;Kitao et al., 2018;Mukherjee et al., 2018;Soukarieh et al., 2020), contain nodes with large areas and orange rings, indicating that they have a very large impact and are still active. ...
Background
Quorum sensing is bacteria’s ability to communicate and regulate their behavior based on population density. Anti-quorum sensing agents (anti-QSA) is promising strategy to treat resistant infections, as well as reduce selective pressure that leads to antibiotic resistance of clinically relevant pathogens. This study analyzes the output, hotspots, and trends of research in the field of anti-QSA against clinically relevant pathogens.
Methods
The literature on anti-QSA from the Web of Science Core Collection database was retrieved and analyzed. Tools such as CiteSpace and Alluvial Generator were used to visualize and interpret the data.
Results
From 1998 to 2023, the number of publications related to anti-QAS research increased rapidly, with a total of 1,743 articles and reviews published in 558 journals. The United States was the largest contributor and the most influential country, with an H-index of 88, higher than other countries. Williams was the most productive author, and Hoiby N was the most cited author. Frontiers in Microbiology was the most prolific and the most cited journal. Burst detection indicated that the main frontier disciplines shifted from MICROBIOLOGY, CLINICAL, MOLECULAR BIOLOGY, and other biomedicine-related fields to FOOD, MATERIALS, NATURAL PRODUCTS, and MULTIDISCIPLINARY. In the whole research history, the strongest burst keyword was cystic-fibrosis patients, and the strongest burst reference was Lee and Zhang (2015). In the latest period (burst until 2023), the strongest burst keyword was silver nanoparticle, and the strongest burst reference was Whiteley et al. (2017). The co-citation network revealed that the most important interest and research direction was anti-biofilm/anti-virulence drug development, and timeline analysis suggested that this direction is also the most active. The key concepts alluvial flow visualization revealed seven terms with the longest time span and lasting until now, namely Escherichia coli , virulence, Pseudomonas aeruginosa , virulence factor, bacterial biofilm, gene expression, quorum sensing. Comprehensive analysis shows that nanomaterials, marine natural products, and artificial intelligence (AI) may become hotspots in the future.
Conclusion
This bibliometric study reveals the current status and trends of anti-QSA research and may assist researchers in identifying hot topics and exploring new research directions.
... Kcal/mol; 0.42 μM; 0.46 Kcal/mol) just lower than the co-crystallized ligand (-9.48 Kcal/mol; 0.11 μM; 0.30 Kcal/mol). This is quite promising for propranolol since the reported experimental inhibitory data for NV5 against the Pqs system was at the nanomolar concentrations (IC50~0.25 μM) [88]. The adopted docking protocol was ensured valid on depicting low aligned RMSD (1.21 Å) following a redocking approach for the co-crystallized ligand depicting the same reported orientation/conformation and conserved contacts with residues ( Figure 7D). ...
... More extended occupation was seen with NV5 for both of the PqsR sub-pockets owing to its larger structure as compared to propranolol. Nevertheless, propranolol managed to be docked at both sub-pockets while maintaining an interaction with Leu207 and Tyr258 being conserved with NV5 and every reported PqsR inhibitor [71,87,88]. Additionally, reported mutagenesis studies, including L207A, L207D, and/or T258A highlighted detrimental activity (~10%) or almost complete activity loss (<2%) for mutant PqsR as compared to the wild-type state [71]. ...
... Kcal/mol; 0.42 µM; 0.46 Kcal/mol) just lower than the co-crystallized ligand (−9.48 Kcal/mol; 0.11 µM; 0.30 Kcal/mol). This is quite promising for propranolol since the reported experimental inhibitory data for NV5 against the Pqs system was at the nanomolar concentrations (IC 50~0 .25 µM) [88]. The adopted docking protocol was ensured valid on depicting low aligned RMSD (1.21 Å) following a redocking approach for the co-crystallized ligand depicting the same reported orientation/conformation and conserved contacts with residues ( Figure 7D). ...
The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting QS systems without significant influence on bacterial growth is assumed as a promising strategy to overcome resistance development. This study aimed at evaluating the anti-QS and anti-virulence activities of the β-adrenoreceptor antagonist propranolol at sub-minimal inhibitory concentrations (sub-MIC) against two Gram-negative bacterial models Pseudomonas aeruginosa and Serratia marcescens. The effect of propranolol on the expression of QS-encoding genes was evaluated. Additionally, the affinity of propranolol to QS receptors was virtually attested. The influence of propranolol at sub-MIC on biofilm formation, motility, and production of virulent factors was conducted. The outcomes of the propranolol combination with different antibiotics were assessed. Finally, the in vivo protection assay in mice was performed to assess propranolol’s effect on lessening the bacterial pathogenesis. The current findings emphasized the significant ability of propranolol at sub-MIC to reduce the formation of biofilms, motility, and production of virulence factors. In addition, propranolol at sub-MIC decreased the capacity of tested bacteria to induce pathogenesis in mice. Furthermore, propranolol significantly downregulated the QS-encoding genes and showed significant affinity to QS receptors. Finally, propranolol at sub-MIC synergistically decreased the MICs of different antibiotics against tested bacteria. In conclusion, propranolol might serve as a plausible adjuvant therapy with antibiotics for the treatment of serious bacterial infections after further pharmacological and pharmaceutical studies.
... With this aim, we conducted a comprehensive computer-based investigation based on molecular docking coupled to 200 ns of molecular dynamics simulation (MD) in explicit solvent. We observed a similar interaction network among the examined compounds that established several contacts with the key residues within the selected binding site [16,[21][22][23][24]. In particular, for compound 11b, we detected an H bond with the sidechain of Q194 and a π-π stacking with the residue Y258. ...
Pseudomonas aeruginosa (PA), one of the ESKAPE pathogens, is an opportunistic Gram-negative bacterium responsible for nosocomial infections in humans but also for infections in patients affected by AIDS, cancer, or cystic fibrosis (CF). Treatment of PA infections in CF patients is a global healthcare problem due to the ability of PA to gain antibiotic tolerance through biofilm formation. Anti-virulence compounds represent a promising approach as adjuvant therapy, which could reduce or eliminate the pathogenicity of PA without impacting its growth. Pyocyanin is one of the virulence factors whose production is modulated by the Pseudomonas quinolone signal (PQS) through its receptor PqsR. Different PqsR modulators have been synthesized over the years, highlighting this new powerful therapeutic strategy. Based on the promising structure of quinazolin-4(3H)-one, we developed compounds 7a–d, 8a,b, 9, 10, and 11a–f able to reduce biofilm formation and the production of virulence factors (pyocyanin and pyoverdine) at 50 µM in two PA strains responsible for CF acute and chronic infections. The developed compounds did not reduce the cell viability of IB3-1 bronchial CF cells, and computational studies confirmed the potential ability of novel compounds to act as potential Pqs system modulators.
... HHQ has previously been shown to affect C. albicans biofilm formation, and it is thought to play an essential role in PA−CA interkingdom interactions. 46 Moreover, CFU counting showed a reduction in CA growth in the presence of PA with a 1−2 log difference in total cell counts. Inhibition of HQNO production suggests potential disruption to the PpqsL enzymatic activity in the PAO1-L pathway; however, this pathway is not disrupted in PA−SA. ...
... In the presence of QSI SEN089 (IC 50 = 67 nM, 46 ), no AQ molecules were detected in the PAO1-L biofilm exometabolomes across all experimental biological and technical repeats, see Figure 3. This suggests that the presence of this inhibitor effectively disrupts the AQ biosynthetic pathway. ...
... Previously, QS molecules production was shown to decrease in planktonic cultures in the presence of various pqs inhibitors. 46,49 Here, we show similar results from a sampling format specifically designed for the analysis of surface-associated microbial communities. This highlights one of the key benefits of our surface-based approach over alternative liquid-based approaches. ...
Previously, metabolites diffused or secreted from microbial samples have been analyzed via liquid chromatography-mass spectrometry (LC-MS) approaches following lengthy extraction protocols. Here, we present a model system for growing biofilms on discs before utilizing rapid and direct surface sampling MS, namely, liquid extraction surface analysis, to study the microbial exometabolome. One of the benefits of this approach is its surface-specific nature, enabling mimicking biofilm formation in a way that the study of planktonic liquid cultures cannot imitate. Even though Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and Candida albicans (C. albicans) have been studied previously in isolation, very few studies consider the complexity of the interplay between these pathogens, which are commonly combined causative agents of infection. Our model system provides a route to investigate changes in the exometabolome, such as metabolites that become circulatory in the presence of multiple pathogens. Our results agree with previous reports showing that 2-alkyl-4(1H)-quinolone signal molecules produced by P. aeruginosa are important markers of infection and suggest that methods for monitoring levels of 2-heptyl-4-hydroxyquinoline and 2,4-dihydroxyquinoline, as well as pyocyanin, could be beneficial in the determination of causative agents in interkingdom infection including P. aeruginosa. Furthermore, studying changes in exometabolome metabolites between pqs quorum sensing antagonists in treated and nontreated samples suggests suppression of phenazine production by P. aeruginosa. Hence, our model provides a rapid analytical approach to gaining a mechanistic understanding of bacterial signaling.
... 19 We previously reported a high-throughput chemical and in silico screening of inhibitors for the Pseudomonas Quinolone Signal (PQS) system, one of three interconnected autoinducing QS systems of P. aeruginosa, resulting in the discovery of several potent QSIs that could attenuate the production of virulence traits that play a key role in the disease process. 14,15,18 However, we found in vitro that their efficacy was substantially reduced against biofilms of this bacterium, due most likely to poor penetration through the matrix. Therefore, in this study we hypothesized that we could enhance the activity of a specific QSI, (R)-2-(4-(3-(6-chloro-4-oxoquinazolin-3(4H)yl)-2-hydroxypropoxy)phenyl)acetonitrile, by conjugating it to a carrier, thus improving delivery throughout the biofilm and enabling potentiation of antibiotic treatment against sessile P. aeruginosa communities. ...
... To investigate the ability of the synthesized polymers to interfere with the Pqs system in PAO1-L, inhibition of a P pqsAlux transcriptional fusion, which reports the PQS-dependent activation of the pqs operon mediated by PqsR, the LysR-type receptor of PQS, 15 was assessed. Pharmacological inhibition of PqsR prevents the formation of the PqsR−PQS complex, leading to less activation of the pqsA promotor and the consequent disruption of the transcription of downstream genes. ...
Antimicrobial resistance (AMR) is a global threat to public health with a forecast of a negative financial impact of one trillion dollars per annum, hence novel therapeutics are urgently needed. The resistance of many bacteria against current drugs is further augmented by the ability of these microbes to form biofilms where cells are encased in a slimy extracellular matrix and either adhered to a surface or forming cell aggregates. Biofilms form physiochemical barriers against the penetration of treatments such as small molecule antibacterials, rendering most treatments ineffective. Pseudomonas aeruginosa, a priority pathogen of immediate concern, controls biofilm formation through multiple layers of gene regulation pathways including quorum sensing (QS), a cell-to-cell signaling system. We have recently reported a series of inhibitors of the PqsR QS regulator from this organism that can potentiate the action of antibiotics. However, these QS inhibitors (QSIs) have shown modest effects on biofilms in contrast with planktonic cultures due to poor penetration through the biofilm matrix. To enhance the delivery of the inhibitors, a small library of polymers was designed as carriers of a specific QSI, with variations in the side chains to introduce either positively charged or neutral moieties to aid penetration into and through the P. aeruginosa biofilm. The synthesized polymers were evaluated in a series of assays to establish their effects on the inhibition of the Pqs QS system in P. aeruginosa, the levels of inhibitor release from polymers, and their impact on biofilm formation. A selected cationic polymer-QSI conjugate was found to penetrate effectively through biofilm layers and to release the QSI. When used in combination with ciprofloxacin, it enhanced the biofilm antimicrobial activity of this antibiotic compared to free QSI and ciprofloxacin under the same conditions.
... In the case of AI-2-based communication, brominated derivatives inhibited activity with an EC50 value below 10 µM, and toxicity against bacteria was very low. Compounds capable of affecting bacterial communication have promising therapeutic potential in the field of regulating bacterial virulence [30]. We also suggest that chlorinated derivatives of flavonoids may be the most promising inhibitors of bacterial communication. ...
A library of previously unknown halogenated derivatives of flavonolignans (silybins A and B, 2,3-dehydrosilybin, silychristin A, and 2,3-dehydrosilychristin A) was prepared. The effect of halogenation on the biological activity of flavonolignans was investigated. Halogenated derivatives had a significant effect on bacteria. All prepared derivatives inhibited the AI-2 type of bacterial communication (quorum sensing) at concentrations below 10 µM. All prepared compounds also inhibited the adhesion of bacteria (Staphyloccocus aureus and Pseudomonas aeruginosa) to the surface, preventing biofilm formation. These two effects indicate that the halogenated derivatives are promising antibacterial agents. Moreover, these derivatives acted synergistically with antibiotics and reduced the viability of antibiotic-resistant S. aureus. Some flavonolignans were able to reverse the resistant phenotype to a sensitive one, implying that they modulate antibiotic resistance.
... M64 (Figure 11d), one of the benzamide-benzimidazole (BB) series compounds, was the first PqsR inhibitor to show in vivo activity; it targeted PqsR and interfered with the early steps of biofilm formation [80]. Through further optimization, 42 (Figure 11d) was designed and reported to act as a potent PqsR antagonist, inhibiting the production of HHQ and PQS at sub-micromolar concentrations [81]. 43 (Figure 11e) is a novel lead QSI and shows high potency, targeting the PqsR of pqs and inhibits the production of pyocyanin [82]. ...
The survival selection pressure caused by antibiotic-mediated bactericidal and bacteriostatic activity is one of the important inducements for bacteria to develop drug resistance. Bacteria gain drug resistance through spontaneous mutation so as to achieve the goals of survival and reproduction. Quorum sensing (QS) is an intercellular communication system based on cell density that can regulate bacterial virulence and biofilm formation. The secretion of more than 30 virulence factors of P. aeruginosa is controlled by QS, and the formation and diffusion of biofilm is an important mechanism causing the multidrug resistance of P. aeruginosa, which is also closely related to the QS system. There are three main QS systems in P. aeruginosa: las system, rhl system, and pqs system. Quorum-sensing inhibitors (QSIs) can reduce the toxicity of bacteria without affecting the growth and enhance the sensitivity of bacterial biofilms to antibiotic treatment. These characteristics make QSIs a popular topic for research and development in the field of anti-infection. This paper reviews the research progress of the P. aeruginosa quorum-sensing system and QSIs, targeting three QS systems, which will provide help for the future research and development of novel quorum-sensing inhibitors.
... 6TPR presented the MvfR LBD structure bound to another possible antagonist found through the optimization of a bacterial cell-based reporter assay hit. Soukarieh and coworkers were able to confirm that 2-[(5-methyl-[1,2,4]triazino [5,6-b]indol-3-yl)sulfanyl]-N-(4-pyridin-2-yloxyphenyl)ethanamide (or NV5) did reduce the biosynthesis of the alkylquinolone AIs even though it was unable to potentiate the effect of ciprofloxacin when combined [47]. ...
Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium responsible for acute and chronic infections in planktonic state or in biofilms. The sessile structures are known to confer physical stability, increase virulence, and work as a protective armor against antimicrobial compounds. P. aeruginosa can control the expression of genes, population density, and biofilm formation through a process called quorum sensing (QS), a rather complex and hierarchical system of communication. A recent strategy to try and overcome bacterial resistance is to target QS proteins. In this study, a combined multi-level computational approach was applied to find possible inhibitors against P. aeruginosa QS regulator protein MvfR, also known as PqsR, using a database of approved FDA drugs, as a repurposing strategy. Fifteen compounds were identified as highly promising putative MvfR inhibitors. On those 15 MvfR ligand complexes, molecular dynamic simulations and MM/GBSA free-energy calculations were performed to confirm the docking predictions and elucidate on the mode of interaction. Ultimately, the five compounds that presented better binding free energies of association than the reference molecules (a known antagonist, M64 and a natural inducer, 2-nonyl-4-hydroxyquinoline) were highlighted as very promising MvfR inhibitors.
