Interdependence of multi-drug efflux pumps and quorum sensing systems in Pseudomonas aeruginosa

ABSTRACT Drug efflux pumps in Pseudomonas aeruginosa were evaluated as potential targets for antibacterial therapy. The potential effects of pump inhibition on susceptibility to fluoroquinolone antibiotics were studied with isogenic strains that overexpress or lack individual efflux pumps and that have various combinations of efflux- and target-mediated mutations. Deletions in three efflux pump operons were constructed. As expected, deletion of the MexAB-OprM efflux pump decreased resistance to fluoroquinolones in the wild-type P. aeruginosa (16-fold reduction for levofloxacin [LVX]) or in the strain that overexpressed mexAB-oprM operon (64-fold reduction for LVX). In addition to that, resistance to LVX was significantly reduced even for the strains carrying target mutations (64-fold for strains for which LVX MICs were >4 μg/ml). We also studied the frequencies of emergence of LVX-resistant variants from different deletion mutants and the wild-type strain. Deletion of individual pumps or pairs of the pumps did not significantly affect the frequency of emergence of resistant variants (at 4× the MIC for the wild-type strain) compared to that for the wild type (10−6to 10−7). In the case of the strain with a triple deletion, the frequency of spontaneous mutants was undetectable (<10−11). In summary, inhibition of drug efflux pumps would (i) significantly decrease the level of intrinsic resistance, (ii) reverse acquired resistance, and (iii) result in a decreased frequency of emergence of P. aeruginosa strains highly resistant to fluoroquinolones in clinical settings.

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Bad Bugs in the XXIst Century: Resistance Mediated by Multi-Drug Efflux Pumps in Gram-Negative Bacteria

10.3389/978-2-88919-931-0 ◽

2016 ◽

Keyword(s):

Efflux Pumps ◽

Gram Negative Bacteria ◽

Drug Efflux ◽

Gram Negative ◽

Xxist Century ◽

Drug Efflux Pumps

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The Role of NIR Fluorescence in MDR Cancer Treatment: From Targeted Imaging to Phototherapy

Current Medicinal Chemistry ◽

10.2174/0929867326666190627123719 ◽

2020 ◽

Vol 27 (33) ◽

pp. 5510-5529

Author(s):

Zengtao Wang ◽

Qingqing Meng ◽

Shaoshun Li

Keyword(s):

Cancer Treatment ◽

Near Infrared ◽

Combined Therapy ◽

Efflux Pumps ◽

Cross Resistance ◽

Great Promise ◽

Drug Efflux ◽

Nir Dyes ◽

Nir Imaging ◽

Drug Efflux Pumps

Background: Multidrug Resistance (MDR) is defined as a cross-resistance of cancer cells to various chemotherapeutics and has been demonstrated to correlate with drug efflux pumps. Visualization of drug efflux pumps is useful to pre-select patients who may be insensitive to chemotherapy, thus preventing patients from unnecessary treatment. Near-Infrared (NIR) imaging is an attractive approach to monitoring MDR due to its low tissue autofluorescence and deep tissue penetration. Molecular NIR imaging of MDR cancers requires stable probes targeting biomarkers with high specificity and affinity. Objective: This article aims to provide a concise review of novel NIR probes and their applications in MDR cancer treatment. Results: Recently, extensive research has been performed to develop novel NIR probes and several strategies display great promise. These strategies include chemical conjugation between NIR dyes and ligands targeting MDR-associated biomarkers, native NIR dyes with inherent targeting ability, activatable NIR probes as well as NIR dyes loaded nanoparticles. Moreover, NIR probes have been widely employed for photothermal and photodynamic therapy in cancer treatment, which combine with other modalities to overcome MDR. With the rapid advancing of nanotechnology, various nanoparticles are incorporated with NIR dyes to provide multifunctional platforms for controlled drug delivery and combined therapy to combat MDR. The construction of these probes for MDR cancers targeted NIR imaging and phototherapy will be discussed. Multimodal nanoscale platform which integrates MDR monitoring and combined therapy will also be encompassed. Conclusion: We believe these NIR probes project a promising approach for diagnosis and therapy of MDR cancers, thus holding great potential to reach clinical settings in cancer treatment.

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Exploiting the metabolic energy demands of drug efflux pumps provides a strategy to overcome multidrug resistance in cancer

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2021.129915 ◽

2021 ◽

Vol 1865 (8) ◽

pp. 129915

Author(s):

Xuexin Gao ◽

Doriane Aguanno ◽

Mary Board ◽

Richard Callaghan

Keyword(s):

Multidrug Resistance ◽

Efflux Pumps ◽

Metabolic Energy ◽

Drug Efflux ◽

Energy Demands ◽

Drug Efflux Pumps

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Pseudomonas aeruginosa Quorum Sensing Systems as Drug Discovery Targets: Current Position and Future Perspectives

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.8b00540 ◽

2018 ◽

Vol 61 (23) ◽

pp. 10385-10402 ◽

Cited By ~ 27

Author(s):

Fadi Soukarieh ◽

Paul Williams ◽

Michael J Stocks ◽

Miguel Cámara

Keyword(s):

Pseudomonas Aeruginosa ◽

Drug Discovery ◽

Quorum Sensing ◽

Future Perspectives ◽

Current Position ◽

Sensing Systems

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The YebC Family Protein PA0964 Negatively Regulates the Pseudomonas aeruginosa Quinolone Signal System and Pyocyanin Production

Journal of Bacteriology ◽

10.1128/jb.00428-08 ◽

2008 ◽

Vol 190 (18) ◽

pp. 6217-6227 ◽

Cited By ~ 72

Author(s):

Haihua Liang ◽

Lingling Li ◽

Zhaolin Dong ◽

Michael G. Surette ◽

Kangmin Duan

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Virulence Factors ◽

Response Regulator ◽

Initial Study ◽

Pfam Family ◽

Swarming Motility ◽

Sensing Systems ◽

Family Protein ◽

Pyocyanin Production

ABSTRACT Bacterial pathogenicity is often manifested by the expression of various cell-associated and secreted virulence factors, such as exoenzymes, protease, and toxins. In Pseudomonas aeruginosa, the expression of virulence genes is coordinately controlled by the global regulatory quorum-sensing systems, which includes the las and rhl systems as well as the Pseudomonas quinolone signal (PQS) system. Phenazine compounds are among the virulence factors under the control of both the rhl and PQS systems. In this study, regulation of the phzA1B1C1D1E1 (phzA1) operon, which is involved in phenazine synthesis, was investigated. In an initial study of inducing conditions, we observed that phzA1 was induced by subinhibitory concentrations of tetracycline. Screening of 13,000 mutants revealed 32 genes that altered phzA1 expression in the presence of subinhibitory tetracycline concentrations. Among them, the gene PA0964, designated pmpR ( p qsR-mediated P QS r egulator), has been identified as a novel regulator of the PQS system. It belongs to a large group of widespread conserved hypothetical proteins with unknown function, the YebC protein family (Pfam family DUF28). It negatively regulates the quorum-sensing response regulator pqsR of the PQS system by binding at its promoter region. Alongside phzA1 expression and phenazine and pyocyanin production, a set of virulence factors genes controlled by both rhl and the PQS were shown to be modulated by PmpR. Swarming motility and biofilm formation were also significantly affected. The results added another layer of regulation in the rather complex quorum-sensing systems in P. aeruginosa and demonstrated a clear functional clue for the YebC family proteins.

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