Evaluation of Heterocyclic Carboxamides as Potential Efflux Pump Inhibitors in Pseudomonas aeruginosa

The ability to rescue the activity of antimicrobials that are no longer effective against bacterial pathogens such as Pseudomonas aeruginosa is an attractive strategy to combat antimicrobial drug resistance. Herein, novel efflux pump inhibitors (EPIs) demonstrating strong potentiation in combination with levofloxacin against wild-type P. aeruginosa ATCC 27853 are presented. A structure activity relationship of aryl substituted heterocyclic carboxamides containing a pentane diamine side chain is described. Out of several classes of fused heterocyclic carboxamides, aryl indole carboxamide compound 6j (TXA01182) at 6.25 µg/mL showed 8-fold potentiation of levofloxacin. TXA01182 was found to have equally synergistic activities with other antimicrobial classes (monobactam, fluoroquinolones, sulfonamide and tetracyclines) against P. aeruginosa. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA01182. TXA01182 was determined to lower the frequency of resistance (FoR) of the partner antimicrobials and enhance the killing kinetics of levofloxacin. Furthermore, TXA01182 demonstrated a synergistic effect with levofloxacin against several multidrug resistant P. aeruginosa clinical isolates.

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An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates

Microbiology ◽

10.1099/mic.0.045716-0 ◽

2011 ◽

Vol 157 (2) ◽

pp. 566-571 ◽

Cited By ~ 17

Author(s):

Abdallah Mahamoud ◽

Jacqueline Chevalier ◽

Milad Baitiche ◽

Elissavet Adam ◽

Jean-Marie Pagès

Keyword(s):

Efflux Pump ◽

Bacterial Species ◽

Efflux Pumps ◽

Multidrug Resistant ◽

Side Chain ◽

Structural Class ◽

Gram Negative ◽

Activity Spectrum ◽

Efflux Pump Inhibitors ◽

Drug Efflux Pump

To date, various bacterial drug efflux pump inhibitors (EPIs) have been described. They exhibit variability in their activity spectrum with respect to antibiotic structural class and bacterial species. Among the various 4-alkylaminoquinazoline derivatives synthesized and studied in this work, one molecule, 1167, increased the susceptibility of important human-pathogenic, resistant, Gram-negative bacteria towards different antibiotic classes. This 4-(3-morpholinopropylamino)-quinazoline induced an increase in the activity of chloramphenicol, nalidixic acid, norfloxacin and sparfloxacin, which are substrates of the AcrAB-TolC and MexAB-OprM efflux pumps that act in these multidrug-resistant isolates. In addition, 1167 increased the intracellular concentration of chloramphenicol in efflux pump-overproducing strains. The rate of restoration depended on the structure of the antibiotic, suggesting that different sites in the efflux pumps may be involved. A molecule exhibiting a morpholine functional group and a propyl extension of the side chain was more active.

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Role of Efflux Pump in Biofilm Formation of Multidrug-Resistant Pseudomonas aeruginosa

4th International Symposium on Innovative Approaches in Health and Sports Sciences Proceedings ◽

10.36287/setsci.4.9.081 ◽

2019 ◽

Author(s):

Ceren Başkan ◽

Belgin Sırıken

Keyword(s):

Pseudomonas Aeruginosa ◽

Biofilm Formation ◽

Efflux Pump ◽

Multidrug Resistant

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Cocktail of CuO, ZnO, or CuZn Nanoparticles and Antibiotics for Combating Multidrug-Resistant Pseudomonas aeruginosa via Efflux Pump Inhibition

ACS Applied Nano Materials ◽

10.1021/acsanm.1c02208 ◽

2021 ◽

Vol 4 (9) ◽

pp. 9799-9810

Author(s):

Ioanna Eleftheriadou ◽

Kleoniki Giannousi ◽

Efthymia Protonotariou ◽

Lemonia Skoura ◽

Minas Arsenakis ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Multidrug Resistant ◽

Efflux Pump Inhibition

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Antimicrobial Compounds of Plant Origin as Efflux Pump Inhibitors: New Avenues for Controlling Multidrug Resistant Pathogens

Journal of Antimicrobial Agents ◽

10.4172/2472-1212.1000159 ◽

2018 ◽

Vol 04 (01) ◽

Cited By ~ 3

Author(s):

Rao M ◽

Padyana S ◽

Dipin KM ◽

Kumar S ◽

Nayak BB ◽

...

Keyword(s):

Efflux Pump ◽

Multidrug Resistant ◽

Antimicrobial Compounds ◽

Plant Origin ◽

Efflux Pump Inhibitors ◽

Multidrug Resistant Pathogens

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Development of an accumulation assay and evaluation of the effects of efflux pump inhibitors on the retention of chlorhexidine digluconate in Pseudomonas aeruginosa and Staphylococcus aureus

BMC Research Notes ◽

10.1186/s13104-017-2637-2 ◽

2017 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Molly Mombeshora ◽

Stanley Mukanganyama

Keyword(s):

Staphylococcus Aureus ◽

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Chlorhexidine Digluconate ◽

Efflux Pump Inhibitors ◽

And Staphylococcus Aureus

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Curcumin as Efflux Pump Inhibitor Agent for Enhancement Treatment Against Multidrug Resistant Pseudomonas aeruginosa Isolates

Iraqi Journal of Science ◽

10.24996/ijs.2020.61.1.6 ◽

2020 ◽

pp. 59-67

Author(s):

Sulaiman D. Sulaiman ◽

Ghusoon A. Abdulhasan

Keyword(s):

Pseudomonas Aeruginosa ◽

Inhibitory Concentration ◽

Efflux Pump ◽

Multidrug Resistant ◽

Diffusion Method ◽

Disc Diffusion Method ◽

Efflux Pump Inhibitor ◽

Before And After ◽

Chromogenic Agar ◽

Susceptibility Patterns

Pseudomonas aeruginosa is considered as a developing opportunistic nosocomial pathogen and is well-known for its multidrug resistance that can be efficiently treated by a combination of antibiotics andefflux pump inhibitors (EPI). Therefore, the purpose of this study was to investigate the effect of curcumin as an EPI for the enhancement of the effectiveness of antibiotics against multidrug resistant (MDR) isolates ofP. aeruginosa. Susceptibility patterns of suspected bacteria was determined using the disc diffusion method andresistant bacteria were identified using chromogenic agar and 16S rDNA. The effectsof curcuminon the enhancement of antibiotics’s activity was evaluated usingthe broth microdilution method.The susceptibility patterns for 50 (67.6%) suspectedP. aeruginosaisolates showed that 36 (72%) of these isolateswere resistant to one of the used antibiotics,whereasonly 21 (42%) were MDR. The highest percentage of resistance was observedtoceftazidime (66%) followed by ciprofloxacin and levofloxacin (40%). Only 35 isolates were specified by chromogenic agar and 16S rDNAas P. aeruginosa.The minimal inhibitory concentration (MIC) of 35 isolates for ciprofloxacin resistant was between 4 and128 µg/ml while for ceftazidime was between 64and 512 µg/ml. After the addition of 50 μg/ml curcumin with ciprofloxacin, there wasa significant increase in the sensitivity (p≤ 0.01) of 13 MDR P.aeroginosa isolates whereas no differences in the sensitivity to ceftazidime were recorded before and after addition ofcurcumin. In conclusion, the results of this study show that curcumin can decrease the MIC value of ciprofloxacin in MDR isolates of P. aeruginosaand can be used as a native compound to enhance the treatment of resistant isolates with ciprofloxacin.

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Molecular mechanisms of efflux pump mediated resistance in clinical isolates of multidrug resistant pseudomonas aeruginosa

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2016.02.269 ◽

2016 ◽

Vol 45 ◽

pp. 104 ◽

Cited By ~ 1

Author(s):

L. Mohanam ◽

L. Priya ◽

E.M. Selvam ◽

S.S. Shivekar ◽

T. Menon

Keyword(s):

Pseudomonas Aeruginosa ◽

Molecular Mechanisms ◽

Efflux Pump ◽

Multidrug Resistant ◽

Clinical Isolates

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QSAR Studies on Bacterial Efflux Pump Inhibitors

Quantitative Structure-Activity Relationships in Drug Design, Predictive Toxicology, and Risk Assessment - Advances in Chemical and Materials Engineering ◽

10.4018/978-1-4666-8136-1.ch007 ◽

2015 ◽

pp. 238-268 ◽

Cited By ~ 1

Author(s):

Khac-Minh Thai ◽

Trong-Nhat Do ◽

Thuy-Viet-Phuong Nguyen ◽

Duc-Khanh-Tho. Nguyen ◽

Thanh-Dao Tran

Keyword(s):

Bacterial Resistance ◽

Efflux Pump ◽

Current Knowledge ◽

Efflux Pumps ◽

Quantitative Structure Activity Relationship ◽

Antimicrobial Drug Resistance ◽

Qsar Studies ◽

Hospital Stays ◽

Efflux Pump Inhibitors

Antimicrobial drug resistance occurs when bacteria undergo certain modifications to eliminate the effectiveness of drugs, chemicals, or other agents designed to cure infections. To date, the burden of resistance has remained one of the major clinical concerns as it renders prolonged and complicated treatments, thereby increasing the medical costs with lengthier hospital stays. Of complex causes for bacterial resistance, there has been increasing evidence that proved the significant role of efflux pumps in antibiotic resistance. Coadministration of Efflux Pump Inhibitors (EPIs) with antibiotics has been considered one of the promising ways not only to improve the efficacy but also to extend the clinical utility of existing antibiotics. This chapter begins with outlining current knowledge about bacterial efflux pumps and drug designs applied in identification of their modulating compounds. Following, the chapter addresses and provides a discussion on Quantitative Structure-Activity Relationship (QSAR) analyses in search of novel and potent efflux pump inhibitors.

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