scholarly journals Influence of P-glycoprotein and MRP efflux pump inhibitors on the intracellular activity of azithromycin and ciprofloxacin in macrophages infected by Listeria monocytogenes or Staphylococcus aureus

2003 ◽  
Vol 51 (5) ◽  
pp. 1167-1173 ◽  
Author(s):  
C. Seral
Keyword(s):  
Staphylococcus Aureus ◽  
Listeria Monocytogenes ◽  
Efflux Pump ◽  
Intracellular Activity ◽  
P Glycoprotein ◽  
Efflux Pump Inhibitors

scholarly journals Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in Human THP-1 Macrophages

2009 ◽  
Vol 53 (9) ◽  
pp. 3734-3743 ◽  
Author(s):  
Sandrine Lemaire ◽  
Françoise Van Bambeke ◽  
Paul M. Tulkens
Keyword(s):  
Staphylococcus Aureus ◽  
Listeria Monocytogenes ◽  
Legionella Pneumophila ◽  
Critical Role ◽  
Intracellular Accumulation ◽  
Cellular Accumulation ◽  
Intracellular Activity ◽  
P Glycoprotein

ABSTRACT CEM-101 is a novel fluoroketolide with lower MICs than those of telithromycin and macrolides. Our aim was to assess the cellular accumulation and intracellular activity of CEM-101 using models developed for analyzing the pharmacokinetics and pharmacological properties of antibiotics against phagocytized bacteria. We used THP-1 macrophages and Staphylococcus aureus (ATCC 25923 [methicillin (meticillin) sensitive]), Listeria monocytogenes (strain EGD), and Legionella pneumophila (ATCC 33153). CEM-101 reached cellular-to-extracellular-concentration ratios of about 350 within 24 h (versus approximately 20, 30, and 160 for telithromycin, clarithromycin, and azithromycin, respectively). This intracellular accumulation was suppressed by incubation at a pH of ≤6 and by monensin (proton ionophore) and was unaffected by verapamil (P-glycoprotein inhibitor; twofold accumulation increase for azithromycin) or gemfibrozil. While keeping with the general properties of the macrolide antibiotics in terms of maximal efficacy (E max; approximately 1-log10-CFU decrease compared to the postphagocytosis inoculum after a 24-h incubation), CEM-101 showed significantly greater potency against phagocytized S. aureus than telithromycin, clarithromycin, and azithromycin (for which the 50% effective concentration [EC50] and static concentrations were about 3-, 6-, and 15-fold lower, respectively). CEM-101 was also about 50-fold and 100-fold more potent than azithromycin against phagocytized L. monocytogenes and L. pneumophila, respectively. These differences in EC50s and static concentrations between drugs were minimized when data were expressed as multiples of the MIC, demonstrating the critical role of intrinsic drug activity (MIC) in eliciting the antibacterial intracellular effects, whereas accumulation per se was unimportant. CEM-101 should show enhanced in vivo potency if used at doses similar to those of the comparators tested here.

Virtual Screening for Novel Staphylococcus Aureus NorA Efflux Pump Inhibitors From Natural Products

2015 ◽  
Vol 11 (2) ◽  
pp. 135-155 ◽  
Author(s):  
Khac-Minh Thai ◽  
Trieu-Du Ngo ◽  
Thien-Vy Phan ◽  
Thanh-Dao Tran ◽  
Ngoc-Vinh Nguyen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Natural Products ◽  
Virtual Screening ◽  
Efflux Pump ◽  
Efflux Pump Inhibitors

Discovery of 4-acetyl-3-(4-fluorophenyl)-1-(p-tolyl)-5-methylpyrrole as a dual inhibitor of human P-glycoprotein and Staphylococcus aureus Nor A efflux pump

2015 ◽  
Vol 13 (19) ◽  
pp. 5424-5431 ◽  
Author(s):  
Jaideep B. Bharate ◽  
Samsher Singh ◽  
Abubakar Wani ◽  
Sadhana Sharma ◽  
Prashant Joshi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Efflux Pump ◽  
Dual Inhibitor ◽  
P Glycoprotein ◽  
Dual Inhibition ◽  
And Staphylococcus Aureus

Pyrroles showed dual inhibition of human P-gp and S. aureus Nor A efflux pump.

Novel DiOC3 96-well real-time efflux assay for discovery of NorA efflux pump inhibitors in Staphylococcus aureus

2021 ◽  
Vol 181 ◽  
pp. 106128
Author(s):  
Najoua Elhidar ◽  
Ahmed Nafis ◽  
André Goehler ◽  
Abdelaziz Abbad ◽  
Lahcen Hassani ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Real Time ◽  
Efflux Pump ◽  
Efflux Pump Inhibitors

scholarly journals Antimicrobial, Anticancer and Multidrug-Resistant Reversing Activity of Novel Oxygen-, Sulfur- and Selenoflavones and Bioisosteric Analogues

2020 ◽  
Vol 13 (12) ◽  
pp. 453
Author(s):  
Małgorzata Anna Marć ◽  
Annamária Kincses ◽  
Bálint Rácz ◽  
Muhammad Jawad Nasim ◽  
Muhammad Sarfraz ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Positive Control ◽  
Biological Evaluation ◽  
Glycoprotein P ◽  
Drug Candidates ◽  
P Glycoprotein ◽  
Efflux Pump Inhibitors

Multidrug resistance of cancer cells to cytotoxic drugs still remains a major obstacle to the success of chemotherapy in cancer treatment. The development of new drug candidates which may serve as P-glycoprotein (P-gp) efflux pump inhibitors is a promising strategy. Selenium analogues of natural products, such as flavonoids, offer an interesting motif from the perspective of drug design. Herein, we report the biological evaluation of novel hybrid compounds, bearing both the flavone core (compounds 1–3) or a bioisosteric analogue core (compounds 4–6) and the triflyl functional group against Gram-positive and Gram-negative bacteria, yeasts, nematodes, and human colonic adenocarcinoma cells. Results show that these flavones and analogues of flavones inhibited the activity of multidrug resistance (MDR) efflux pump ABCB1 (P-glycoprotein, P-gp). Moreover, the results of the rhodamine 123 accumulation assay demonstrated a dose-dependent inhibition of the abovementioned efflux pump. Three compounds (4, 5, and 6) exhibited potent inhibitory activity, much stronger than the positive control, verapamil. Thus, these chalcogen bioisosteric analogues of flavones become an interesting class of compounds which could be considered as P-gp efflux pump inhibitors in the therapy of MDR cancer. Moreover, all the compounds served as promising adjuvants in the cancer treatment, since they exhibited the P-gp efflux pump modulating activity.

An Update on Staphylococcus aureus NorA Efflux Pump Inhibitors

2020 ◽  
Vol 20 (24) ◽  
pp. 2168-2185
Author(s):  
Kadja Luana Chagas Monteiro ◽  
Thiago Mendonça de Aquino ◽  
Francisco Jaime B. Mendonça Junior
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Resistance ◽  
Efflux Pump ◽  
Control Strategies ◽  
Structural Diversity ◽  
Multidrug Resistant ◽  
Efflux Pump Inhibitors ◽  
Vancomycin Resistant ◽  
Sulfur Containing ◽  
Substantial Degree

Background: Methicillin-resistant and vancomycin-resistant Staphylococcus aureus are pathogens causing severe infectious diseases that pose real public health threats problems worldwide. In S. aureus, the most efficient multidrug-resistant system is the NorA efflux pump. For this reason, it is critical to identify efflux pump inhibitors. Objective: In this paper, we present an update of the new natural and synthetic compounds that act as modulators of antibiotic resistance through the inhibition of the S. aureus NorA efflux pump. Results: Several classes of compounds capable of restoring the antibiotic activity have been identified against resistant-S. aureus strains, acting as NorA efflux pump inhibitors. The most promising classes of compounds were quinolines, indoles, pyridines, phenols, and sulfur-containing heterocycles. However, the substantial degree structural diversity of these compounds makes it difficult to establish good structure- activity correlations that allow the design of compounds with more promising activities and properties. Conclusion: Despite substantial efforts put forth in the search for new antibiotic adjuvants that act as efflux pump inhibitors, and despite several promising results, there are currently no efflux pump inhibitors authorized for human or veterinary use, or in clinical trials. Unfortunately, it appears that infection control strategies have remained the same since the discovery of penicillin, and that most efforts remain focused on discovering new classes of antibiotics, rather than trying to prolong the life of available antibiotics, and simultaneously fighting mechanisms of bacterial resistance.

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