scholarly journals An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates

Microbiology ◽  
2011 ◽  
Vol 157 (2) ◽  
pp. 566-571 ◽  
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.

A Tobramycin Vector Enhances Synergy and Efficacy of Efflux Pump Inhibitors against Multidrug-Resistant Gram-Negative Bacteria

2017 ◽  
Vol 60 (9) ◽  
pp. 3913-3932 ◽  
Author(s):  
Xuan Yang ◽  
Sudeep Goswami ◽  
Bala Kishan Gorityala ◽  
Ronald Domalaon ◽  
Yinfeng Lyu ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Efflux Pump Inhibitors

scholarly journals Efflux Pump Mediated Antimicrobial Resistance by Staphylococci in Health-Related Environments: Challenges and the Quest for Inhibition

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1502
Author(s):  
Abolfazl Dashtbani-Roozbehani ◽  
Melissa H. Brown
Keyword(s):  
Antimicrobial Resistance ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Current Knowledge ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Multidrug Efflux Pump ◽  
New Antibiotics ◽  
Efflux Pump Inhibitors

The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with increased use of sanitisers and disinfectants due to the ongoing COVID-19 pandemic can further aggravate the problem of antimicrobial resistance. Staphylococci utilise multiple mechanisms to circumvent the effects of antimicrobials. One of these resistance mechanisms is the export of antimicrobial agents through the activity of membrane-embedded multidrug efflux pump proteins. The use of efflux pump inhibitors in combination with currently approved antimicrobials is a promising strategy to potentiate their clinical efficacy against resistant strains of staphylococci, and simultaneously reduce the selection of resistant mutants. This review presents an overview of the current knowledge of staphylococcal efflux pumps, discusses their clinical impact, and summarises compounds found in the last decade from plant and synthetic origin that have the potential to be used as adjuvants to antibiotic therapy against multidrug resistant staphylococci. Critically, future high-resolution structures of staphylococcal efflux pumps could aid in design and development of safer, more target-specific and highly potent efflux pump inhibitors to progress into clinical use.

scholarly journals Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates

2003 ◽  
Vol 376 (3) ◽  
pp. 801-805 ◽  
Author(s):  
Monique MALLÉA ◽  
Abdallah MAHAMOUD ◽  
Jacqueline CHEVALIER ◽  
Sandrine ALIBERT-FRANCO ◽  
Pierre BROUANT ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Microbial Pathogens ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
High Level ◽  
Antibiotic Efflux

Over the last decade, MDR (multidrug resistance) has increased worldwide in microbial pathogens by efflux mechanisms, leading to treatment failures in human infections. Several Gram-negative bacteria efflux pumps have been described. These proteinaceous channels are capable of expelling structurally different drugs across the envelope and conferring antibiotic resistance in various bacterial pathogens. Combating antibiotic resistance is an urgency and the blocking of efflux pumps is an attractive response to the emergence of MDR phenotypes in infectious bacteria. In the present study, various alkylaminoquinolines were tested as potential inhibitors of drug transporters. We showed that alkylaminoquinolines are capable of restoring susceptibilities to structurally unrelated antibiotics in clinical isolates of MDR Gram-negative bacteria. Antibiotic efflux studies indicated that 7-nitro-8-methyl-4-[2´-(piperidino)ethyl]aminoquinoline acts as an inhibitor of the AcrAB–TolC efflux pump and restores a high level of intracellular drug concentration. Inhibitory activity of this alkylaminoquinoline is observed on clinical isolates showing different resistance phenotypes.

scholarly journals The Action of Efflux Pump Genes in Conferring Drug Resistance to Klebsiella Species and Their Inhibition

2021 ◽  
Author(s):  
Priyanka Ashwath ◽  
Akhila Dharnappa Sannejal
Keyword(s):  
Drug Resistance ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Acquired Resistance ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Klebsiella Species ◽  
Gram Negative ◽  
Multidrug Efflux Pumps

AbstractNosocomial infections caused by Klebsiella species are characterized by high rates of morbidity and mortality. The emergence of the multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative bacteria reduces the antibiotic efficacy in the treatment of infections caused by the microorganisms. Management of these infections is often difficult, due to the high frequency of strains resistant to multiple antimicrobial agents. Multidrug efflux pumps play a major role as a mechanism of antimicrobial resistance in Gram-negative pathogens. Efflux systems are significant in conferring intrinsic and acquired resistance to the bacteria. The emergence of increasing drug resistance among Klebsiella pneumoniae nosocomial isolates has limited the therapeutic options for treatment of these infections and hence there is a constant quest for an alternative. In this review, we discuss various resistance mechanisms, focusing on efflux pumps and related genes in conferring resistance to Klebsiella. The role of various efflux pump inhibitors (EPIs) in restoring the antibacterial activity has also been discussed. In specific, antisense oligonucleotides as alternative therapeutics in combatting efflux-mediated resistance in Klebsiella species have focused upon.

scholarly journals Effects of Efflux Pump Inhibitors on Colistin Resistance in Multidrug-Resistant Gram-Negative Bacteria

2016 ◽  
Vol 60 (5) ◽  
pp. 3215-3218 ◽  
Author(s):  
Wentao Ni ◽  
Yanjun Li ◽  
Jie Guan ◽  
Jin Zhao ◽  
Junchang Cui ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Colistin Resistance ◽  
Gram Negative ◽  
Content Type ◽  
Resistant Strains ◽  
Efflux Pump Inhibitors ◽  
Time Kill

ABSTRACTWe tested the effects of various putative efflux pump inhibitors on colistin resistance in multidrug-resistant Gram-negative bacteria. Addition of 10 mg/liter cyanide 3-chlorophenylhydrazone (CCCP) to the test medium could significantly decrease the MICs of colistin-resistant strains. Time-kill assays showed CCCP could reverse colistin resistance and inhibit the regrowth of the resistant subpopulation, especially inAcinetobacter baumanniiandStenotrophomonas maltophilia. These results suggest colistin resistance in Gram-negative bacteria can be suppressed and reversed by CCCP.

scholarly journals Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 774
Author(s):  
Martijn Zwama ◽  
Kunihiko Nishino
Keyword(s):  
Legionella Pneumophila ◽  
Bacterial Infections ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Bacterial Strains ◽  
Gram Negative ◽  
Over Expression ◽  
Wide Range ◽  
Resistance Nodulation Division

The rise in multidrug resistance (MDR) is one of the greatest threats to human health worldwide. MDR in bacterial pathogens is a major challenge in healthcare, as bacterial infections are becoming untreatable by commercially available antibiotics. One of the main causes of MDR is the over-expression of intrinsic and acquired multidrug efflux pumps, belonging to the resistance-nodulation-division (RND) superfamily, which can efflux a wide range of structurally different antibiotics. Besides over-expression, however, recent amino acid substitutions within the pumps themselves—causing an increased drug efflux efficiency—are causing additional worry. In this review, we take a closer look at clinically, environmentally and laboratory-evolved Gram-negative bacterial strains and their decreased drug sensitivity as a result of mutations directly in the RND-type pumps themselves (from Escherichia coli, Salmonella enterica, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Acinetobacter baumannii and Legionella pneumophila). We also focus on the evolution of the efflux pumps by comparing hundreds of efflux pumps to determine where conservation is concentrated and where differences in amino acids can shed light on the broad and even broadening drug recognition. Knowledge of conservation, as well as of novel gain-of-function efflux pump mutations, is essential for the development of novel antibiotics and efflux pump inhibitors.

scholarly journals Sensitizing multi drug resistant Staphylococcus aureus isolated from surgical site infections to antimicrobials by efflux pump inhibitors

2020 ◽  
Vol 20 (4) ◽  
pp. 1632-45
Author(s):  
Baiomy Amr A ◽  
Shaker Ghada H ◽  
Abbas Hisham A
Keyword(s):  
Staphylococcus Aureus ◽  
Multidrug Resistance ◽  
Ethidium Bromide ◽  
Efflux Pump ◽  
Surgical Site Infections ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Minor Role ◽  
Efflux Pump Inhibitors ◽  
A Minor

Background: Staphylococcus aureus is a common hospital acquired infections pathogen. Multidrug-resistant Methicillin-resist- ant Staphylococcus aureus represents a major problem in Egyptian hospitals. The over-expression of efflux pumps is a main cause of multidrug resistance. The discovery of efflux pump inhibitors may help fight multidrug resistance by sensitizing bacteria to antibiotics. This study aimed to investigate the role of efflux pumps in multidrug resistance. Methods: Twenty multidrug resistant S. aureus isolates were selected. Efflux pumps were screened by ethidium bromide agar cartwheel method and polymerase chain reaction. The efflux pump inhibition by seven agents was tested by ethidium bromide agar cartwheel method and the effect on sensitivity to selected antimicrobials was investigated by broth microdilu- tion method. Results: Seventy percent of isolates showed strong efflux activity, while 30% showed intermediate activity. The efflux genes mdeA, norB, norC, norA and sepA were found to play the major role in efflux, while genes mepA, smr and qacA/B had a minor role. Verapamil and metformin showed significant efflux inhibition and increased the sensitivity to tested antimicrobials, while vildagliptin, atorvastatin, domperidone, mebeverine and nifuroxazide showed no effect. Conclusion: Efflux pumps are involved in multidrug resistance in Staphylococcus aureus. Efflux pump inhibitors could increase the sensitivity to antimicrobials. Keywords: Staphylococcus aureus; multidrug resistance; efflux pump inhibitors.

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

Antibiotics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 30
Author(s):  
Yi Yuan ◽  
Jesus D. Rosado-Lugo ◽  
Yongzheng Zhang ◽  
Pratik Datta ◽  
Yangsheng Sun ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Side Chain ◽  
Genetic Studies ◽  
Antimicrobial Drug Resistance ◽  
Efflux Pump Inhibitors ◽  
Relationship Of ◽  
Kinetics Of ◽  
Rule Out

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.

scholarly journals Chalcones Isolated from Arrabidaea brachypoda Flowers as Inhibitors of NorA and MepA Multidrug Efflux Pumps of Staphylococcus aureus

Antibiotics ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 351 ◽  
Author(s):  
Luís Mário Rezende-Júnior ◽  
Leila Maria de Sousa Andrade ◽  
Antonio Linkoln Alves Borges Leal ◽  
Avilnete Belem de Souza Mesquita ◽  
Ana Lurdes Portela de Araújo dos Santos ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Binding Sites ◽  
Bacterial Resistance ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Public Health Issue ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pumps ◽  
Efflux Pump Inhibitors

Bacterial resistance to antibiotics has become a public health issue around the world. The present study aimed to evaluate the antibacterial activity of chalcones isolated from flowers of Arrabidaea brachypoda, and their potential as efflux pump inhibitors of Staphylococcus aureus efflux pumps. Microdilution assays were performed with natural products from A. brachypoda. Chalcones 1, 3, 4, and 5 did not show intrinsic antimicrobial activity against all S. aureus strains tested, but they were able to potentiate the Norfloxacin action against the SA1199-B (norA) strain, with a better modulating action for the 4 trimethoxylated chalcone. All chalcones were also able to potentiate the action of EtBr against SA1199-B strain, suggesting a potential NorA inhibition. Moreover, chalcone 4 was able to interfere in the activity of MepA, and interfered weakly in the QacA/B activity. Molecular docking analyzes showed that tested chalcones are capable of binding in the hydrophobic cavity of NorA and MepA, in the same Norfloxacin binding site, indicating that chalcone 4 compete with the antibiotic for the same NorA and MepA binding sites. Association of chalcone 4 with Norfloxacin could be an alternative against multidrug resistant S. aureus over-productive of NorA or MepA.

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