scholarly journals Investigation on the effect of known potent S. aureus NorA efflux pump inhibitors on the staphylococcal biofilm formation

RSC Advances ◽  
2017 ◽  
Vol 7 (59) ◽  
pp. 37007-37014 ◽  
Author(s):  
Stefano Sabatini ◽  
Miranda Piccioni ◽  
Tommaso Felicetti ◽  
Stefania De Marco ◽  
Giuseppe Manfroni ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Efflux Pump Inhibitors

The emergence of multidrug resistant microorganisms has triggered the impending need of developing effective antibacterial strategies.

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 MmpL3 Is the Cellular Target of the Antitubercular Pyrrole Derivative BM212

2011 ◽  
Vol 56 (1) ◽  
pp. 324-331 ◽  
Author(s):  
Valentina La Rosa ◽  
Giovanna Poce ◽  
Julio Ortiz Canseco ◽  
Silvia Buroni ◽  
Maria Rosalia Pasca ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Smegmatis ◽  
Efflux Pump ◽  
Protein A ◽  
Multidrug Resistant ◽  
Whole Genome ◽  
Content Type ◽  
Genomic Libraries ◽  
Cellular Target ◽  
Efflux Pump Inhibitors

ABSTRACTThe 1,5-diarylpyrrole derivative BM212 was previously shown to be active against multidrug-resistant clinical isolates andMycobacterium tuberculosisresiding within macrophages as well as againstMycobacterium aviumand other atypical mycobacteria. To determine its mechanism of action, we identified the cellular target. SpontaneousMycobacterium smegmatis,Mycobacterium bovisBCG, andM. tuberculosisH37Rv mutants that were resistant to BM212 were isolated. By the screening of genomic libraries and by whole-genome sequencing, we found that all the characterized mutants showed mutations in themmpL3gene, allowing us to conclude that resistance to BM212 maps to the MmpL3 protein, a member of the MmpL (mycobacterialmembraneprotein,large) family. Susceptibility was unaffected by the efflux pump inhibitors reserpine, carbonylcyanidem-chlorophenylhydrazone, and verapamil. Uptake/efflux experiments with [14C]BM212 demonstrated that resistance is not driven by the efflux of BM212. Together, these data strongly suggest that the MmpL3 protein is the cellular target of BM212.

scholarly journals Trp-Containing Antibacterial Peptides Impair Quorum Sensing and Biofilm Development in Multidrug-Resistant Pseudomonas aeruginosa and Exhibit Synergistic Effects With Antibiotics

2021 ◽  
Vol 12 ◽  
Author(s):  
Dejing Shang ◽  
Xue Han ◽  
Wanying Du ◽  
Zhiru Kou ◽  
Fengquan Jiang
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibacterial Activity ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Synergistic Effects ◽  
Multidrug Resistant ◽  
Biofilm Development ◽  
Antibiotic Efflux

Pseudomonas aeruginosa uses quorum sensing (QS) to control virulence, biofilm formation and antibiotic efflux pump expression. The development of effective small molecules targeting the QS system and biofilm formation represents a novel attractive strategy. In this present study, the effects of a series of Trp-containing peptides on the QS-regulated virulence and biofilm development of multidrug-resistant P. aeruginosa, as well as their synergistic antibacterial activity with three classes of traditional chemical antibiotics were investigated. The results showed that Trp-containing peptides at low concentrations reduced the production of QS-regulated virulence factors by downregulating the gene expression of both the las and rhl systems in the strain MRPA0108. Biofilm formation was inhibited in a concentration-dependent manner, which was associated with extracellular polysaccharide production inhibition by downregulating pelA, algD, and pslA transcription. These changes correlated with alterations in the extracellular production of pseudomonal virulence factors and swarming motility. In addition, the combination of Trp-containing peptides at low concentration with the antibiotics ceftazidime and piperacillin provided synergistic effects. Notably, L11W and L12W showed the highest synergy with ceftazidime and piperacillin. A mechanistic study demonstrated that the Trp-containing peptides, especially L12W, significantly decreased β-lactamase activity and expression of efflux pump genes OprM, MexX, and MexA, resulting in a reduction in antibiotic efflux from MRPA0108 cells and thus increasing the antibacterial activity of these antibiotics against MRPA0108.

scholarly journals EVALUATION OF EFFLUX PUMP ACTIVITY AND BIOFILM FORMATION IN MULTIDRUG RESISTANT KLEBSIELLA PNEUMONIAE ISOLATES IN TANTA, EGYPT

2021 ◽  
Vol 12 (3) ◽  
pp. 1-5
Author(s):  
Tarek El-Said El-Banna ◽  
Fatma Ibrahim Sonbol ◽  
Heba M El-Dawy ◽  
Lamiaa A Al-Madboly
Keyword(s):  
Drug Resistance ◽  
Klebsiella Pneumoniae ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
High Morbidity ◽  
Biochemical Tests ◽  
Antibiotic Resistance Profile ◽  
Pump Activity

Nosocomial and community acquired infections that caused by multidrug-resistant (MDR) Klebsiella pneumoniae isolates are widespread recently resulting in high morbidity and mortality due to limited number of treatment options with effective antibiotics. The aim of this study is to evaluate the antibiotic resistance profile, biofilm formation and efflux pump activity of MDR K. pneumoniae isolates collected from different hospitals in Tanta, Egypt. A total of 70 K. pneumoniae isolates characterized by standard biochemical tests and confirmed by MALDI-TOF/MS were screened for antibiotic susceptibility, efflux pump activity and biofilm formation. Isolates displayed high resistance to penicillins, cephalosporins, trimethoprim-sulfamethoxazole and the majority of tested fluoro/-quinolones and decreased resistance to imipenem, amikacin, chloramphenicol, tigecycline and colistin. Out of 70 K. pneumoniae isolates, 2 isolates exhibited Pan Drug-Resistance (PDR) profile while 57 (81.4%) and 11 (15.7%) exhibited MDR and Extensively drug-resistance (XDR) profiles, respectively. Sixty-four (91.4%) isolates exhibited efflux pump activity while all tested isolates had the ability to form biofilm with varied degrees as 40 (57.1%), 26 (37.1%), and 4 (5.7%) isolates were strong, moderate and weak biofilm producers, respectively. Also, a strong relation between efflux pump activity and biofilm formation per isolate was detected. In conclusion, Multidrug resistance, biofilm formation and efflux pump capabilities in K. pneumoniae have serious public health implications in the management and control of infections caused by this bacterium. Therefore, a multifaceted approach and precise planning are recommended in controlling these infections

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 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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