Effect of efflux pump inhibition on Pseudomonas aeruginosa transcriptome and virulence

Rampioni, Giordano; Pillai, Cejoice Ramachandran; Longo, Francesca; Bondì, Roslen; Baldelli, Valerio; Messina, Marco; Imperi, Francesco; Visca, Paolo; Leoni, Livia

doi:10.1038/s41598-017-11892-9

Cited by 77 publications

(69 citation statements)

References 52 publications

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“…Since the average weight of G. mellonella larvae was ca. 500 mg, and arbitrarily assuming uniform dispersal of injected bacteria and clofoctol in 500 l of larval volume (64,65), 10 l of saline containing 5 mM clofoctol was injected to yield 100 M clofoctol in each larva. Preliminarily, we verified that the injection of 10 l of saline containing 5 mM clofoctol did not affect the survival of uninfected larvae and that 2 h of incubation of P. aeruginosa with 5 mM clofoctol did not affect P. aeruginosa growth and viability (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa

D’Angelo

Baldelli

Halliday

et al. 2018

Antimicrob Agents Chemother

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The long-term use of antibiotics has led to the emergence of multidrug-resistant bacteria. A promising strategy to combat bacterial infections aims at hampering their adaptability to the host environment without affecting growth. In this context, the intercellular communication system quorum sensing (QS), which controls virulence factor production and biofilm formation in diverse human pathogens, is considered an ideal target. Here, we describe the identification of new inhibitors of the QS system of the human pathogen by screening a library of 1,600 U.S. Food and Drug Administration-approved drugs. Phenotypic characterization of engineered strains and molecular docking demonstrated that the antifungal drugs clotrimazole and miconazole, as well as an antibacterial compound active against Gram-positive pathogens, clofoctol, inhibit the system, probably by targeting the transcriptional regulator PqsR. The most active inhibitor, clofoctol, specifically inhibited the expression of-controlled virulence traits in , such as pyocyanin production, swarming motility, biofilm formation, and expression of genes involved in siderophore production. Moreover, clofoctol protected larvae from infection and inhibited the QS system in isolates from cystic fibrosis patients. Notably, clofoctol is already approved for clinical treatment of pulmonary infections caused by Gram-positive bacterial pathogens; hence, this drug has considerable clinical potential as an antivirulence agent for the treatment of lung infections.

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Section: Resultsmentioning

confidence: 99%

Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa

D’Angelo

Baldelli

Halliday

et al. 2018

Antimicrob Agents Chemother

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“…Fourth, plants produce both antibacterial compounds and EPIs that improve their antibacterial activity, for example, antibiotic berberine and EPI 5′‐methoxyhydnocarpin (5′‐MHC) in Berberis vulgaris , antibiotic α‐linolenic acid and isoflavone‐based EPIs in Lupinus argenteus , and antibiotic dalversinol A and EPI methoxychalcone in Dalea versicolor , although EPI may not be a primary functional role of some plant natural products . In addition, EPIs may also have an impact on quorum sensing and virulence . Recent studies have highlighted the importance of efflux pumps in the formation of bacterial persisters .…”

Section: Introductionmentioning

confidence: 99%

“…[51][52][53] In addition, EPIs may also have an impact on quorum sensing and virulence. 54 Recent studies have highlighted the importance of efflux pumps in the formation of bacterial persisters. 55,56 A significantly higher expression of multidrug efflux-associated genes was found in persisters and their formation was largely reduced in efflux knockout strains.…”

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confidence: 99%

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

141

127

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Bacterial infections are an increasingly serious issue worldwide. The inability of existing therapies to treat multidrug‐resistant pathogens has been recognized as an important challenge of the 21st century. Efflux pumps are important in both intrinsic and acquired bacterial resistance and identification of small molecule efflux pump inhibitors (EPIs), capable of restoring the effectiveness of available antibiotics, is an active research field. In the last two decades, much effort has been made to identify novel EPIs. However, none of them has so far been approved for therapeutic use. In this article, we explore different structural families of currently known EPIs for multidrug resistance efflux systems in the most extensively studied pathogens (NorA in Staphylococcus aureus, AcrAB‐TolC in Escherichia coli, and MexAB‐OprM in Pseudomonas aeruginosa). Both synthetic and natural compounds are described, with structure‐activity relationship studies and optimization processes presented systematically for each family individually. In vitro activities against selected test strains are presented in a unifying manner for all the EPIs described, together with the most important toxicity, pharmacokinetic and in vivo efficacy data. A critical evaluation of lead‐likeness characteristics and the potential for clinical development of the most promising inhibitors of the three efflux systems is described. This overview of EPIs is a good starting point for the identification of novel effective antibacterial drugs.

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“…38,39 OdDHL is a MexAB-OprM substrate 40 and mutants of this pump are unable to transport this AI; hence, it results in decreased expression of Las regulated virulence factors. 41 MexEF-OprN and MexGHI play an indirect role in QS by secreting anthranilate, which is a toxic metabolite and a PQS precursor. 42 C 4 -homoserine lactone (C4HSL) overexpresses MexAB-OprM.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Quorum-Sensing and Efflux Pumps Interactions in Pseudomonas aeruginosa Against Photooxidative Stress

Rezaie¹,

Pourhajibagher²,

Chiniforush³

et al. 2018

J Lasers Med Sci

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Quorum SensingCommunication between similar or different species occurs via various chemical signals produced and secreted by the bacteria. These signals can be population dependent (QS) or can be secreted during several proliferation stages (e.g., indole, which is secreted in the stationary phase by Escherichia coli). AbstractResistant infections essentially cause mortality in a burn unit. Several bacteria contribute to burn infections; among these, Pseudomonas aeruginosa majorly contributes to these infections revealing significant drug resistance. Similar to other bacteria, P. aeruginosa reveals various mechanisms to attain highest pathogenicity and resistance; among these, efflux pumps and quorum sensing are crucial. Quorum sensing enables effective communication between bacteria and synchronizes their gene expression resulting in optimum effect of the secreted proteins; alternatively, efflux pumps increase the bacterial resistance by pumping out the antimicrobial factors as well as the QS signals and precursors. Of recent, increasing episodes of drug resistance led to new findings and approaches for killing pathogenic bacteria without inducing the drug-resistant species. Photodynamic therapy (PDT), considered as an adjuvant and innovative method for conventional antibiotic therapy, is a photochemical reaction that includes visible light, oxygen, and a photosensitizer (PS). In this therapy, after exposure to visible light, the PS generates reactive oxygen species (ROS) that are bacteriostatic or bactericidal. Furthermore, this oxidative stress can disrupt the coordination of gene expression and alter the bacterial behavior. Considering the fact that the adaption and several gene expression patterns of microorganisms within the biofilm make them notably resistant to the recent antimicrobial treatments, this study aimed to emphasize the relationship between the efflux pump and QS under oxidative stress and their role in P. aeruginosa's reaction to PDT.

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Effect of efflux pump inhibition on Pseudomonas aeruginosa transcriptome and virulence

Cited by 77 publications

References 52 publications

Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa

Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

The Effect of Quorum-Sensing and Efflux Pumps Interactions in Pseudomonas aeruginosa Against Photooxidative Stress

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