MexAB-OprM-Specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: Discovery and early strategies for lead optimization

2003 ◽  
Vol 13 (23) ◽  
pp. 4201-4204 ◽  
Author(s):  
Kiyoshi Nakayama ◽  
Yohei Ishida ◽  
Masami Ohtsuka ◽  
Haruko Kawato ◽  
Ken-ichi Yoshida ◽  
...  
2020 ◽  
pp. AAC.02028-20
Author(s):  
Gang W. Wang ◽  
Jean-Michel Brunel ◽  
Jean-Michel Bolla ◽  
Françoise Van Bambeke

Active efflux confers intrinsic resistance to multiple antibiotics in Pseudomonas aeruginosa, including old disused molecules. Beside resistance, intracellular survival is another reason for failure to eradicate bacteria with antibiotics. We evaluated the capacity of polyaminoisoprenyl potentiators (designed as efflux pump inhibitors [EPIs]) NV716 and NV731 compared to PAβN to restore the activity of disused antibiotics (doxycycline, chloramphenicol [substrates for efflux], rifampin [not substrate]) in comparison with ciprofloxacin against intracellular P. aeruginosa (strains with variable efflux levels) in THP-1 monocytes exposed during 24h to antibiotics alone (0.003-100x MIC) or combined with EPIs. Pharmacodynamic parameters (apparent static concentrations [Cs]; maximal relative efficacy [Emax]) were calculated using the Hill equation of concentration-response curves. PAβN and NV731 moderately reduced (0-4 doubling dilutions) antibiotic MICs but did not affect their intracellular activity. NV716 markedly reduced (1-16 doubling dilutions) the MIC of all antibiotics (substrates or not for efflux; strains expressing efflux or not); it improved their relative potency and maximal efficacy (lower Cs; more negative Emax) intracellularly. In parallel, NV716 reduced the persister fraction in stationary cultures when combined with ciprofloxacin. In contrast to PAβN and NV731 that act as EPIs against extracellular bacteria only, NV716 can resensitize P. aeruginosa to antibiotics whether substrates or not for efflux, both extracellularly and intracellularly. This suggests a complex mode of action that goes beyond a simple inhibition of efflux and reduces bacterial persistence. NV716 may appear as a useful adjuvant, including to disused antibiotics with low antipseudomonal activity, to improve their activity, including against intracellular P. aeruginosa.


2002 ◽  
Vol 12 (5) ◽  
pp. 763-766 ◽  
Author(s):  
Thomas E. Renau ◽  
Roger Léger ◽  
Rose Yen ◽  
Miles W. She ◽  
Eric M. Flamme ◽  
...  

2001 ◽  
Vol 11 (5) ◽  
pp. 663-667 ◽  
Author(s):  
Thomas E Renau ◽  
Roger Léger ◽  
Eric M Flamme ◽  
Miles W She ◽  
Carla L Gannon ◽  
...  

ChemInform ◽  
2010 ◽  
Vol 33 (25) ◽  
pp. no-no
Author(s):  
Thomas E. Renau ◽  
Roger Leger ◽  
Rose Yen ◽  
Miles W. She ◽  
Eric M. Flamme ◽  
...  

2016 ◽  
Vol 10 (06) ◽  
pp. 600-604 ◽  
Author(s):  
Mahshid Talebi-Taher ◽  
َAli Majidpour ◽  
Abbas Gholami ◽  
Samira Rasouli-Kouhi ◽  
Maryam Adabi

Introduction: Multidrug resistance in Pseudomonas aeruginosa may be due to efflux pump overexpression. This study phenotypically examined the role of efflux pump inhibitors in decreasing antibiotic cross-resistance between beta-lactams, fluoroquinolones, and aminoglycosides in P. aeruginosa isolates from burn patients in Iran. Methodology: A total of 91 phenotypically and genotypically confirmed P. aeruginosa samples were studied. Multidrug cross-resistance was determined using the disk diffusion method and minimum inhibitory concentration (MIC) test. The contribution of efflux pumps was determined by investigating MIC reduction assay to markers of beta-lactams, fluoroquinolones, and aminoglycosides in the absence and presence of an efflux pump inhibitor. All the isolates were also tested by polymerase chain reaction for the presence of mexA, mexC, and mexE efflux genes. Results: Of the isolates, 81 (89%) and 83 (91.2%) were multidrug resistant according to the disk diffusion and MIC method, respectively. Cross-resistance was observed in 67 (73.6%) and 68 (74.7%) of isolates according to the disk diffusion and MIC method, respectively. In the presence of the efflux pump inhibitor, twofold or higher MIC reduction to imipenem, cefepime, ciprofloxacin, and gentamicin was observed in 59, 65, 55, and 60 isolates, respectively. Except for two isolates that were negative for mexC, all isolates were positive for mexA, mexC, and mexE genes simultaneously. Conclusion: Efflux pumps could cause different levels of resistance based on their expression in clinical isolates. Early detection of different efflux pumps in P. aeruginosa could allow the use of other antibiotics and efflux pump inhibitors in combination with antibiotic therapy.


2011 ◽  
Vol 6 (1) ◽  
pp. 5870 ◽  
Author(s):  
Momen Askoura ◽  
Walid Mattawa ◽  
Turki Abujamel ◽  
Ibrahim Taher

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