scholarly journals Identified Seaweed Compound Diphenylmethane Serves as an Efflux Pump Inhibitor in Drug-Resistant Escherichia coli

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1378
Author(s):  
Wen-Jung Lu ◽  
Pang-Hung Hsu ◽  
Chun-Ju Chang ◽  
Cheng-Kuan Su ◽  
Yan-Jyun Huang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Major Elements ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Cell Toxicity ◽  
Efflux Pump Inhibitor ◽  
E Coli ◽  
Drug Efflux Pumps ◽  
Time Kill

Drug efflux pumps are one of the major elements used by antibiotic-resistant bacteria. Efflux pump inhibitors (EPIs) are potential therapeutic agents for adjunctive therapy, which can restore the activity of antibiotics that are no longer effective against pathogens. This study evaluated the seaweed compound diphenylmethane (DPM) for its EPI activity. The IC50 and modulation results showed that DPM has no antibacterial activity but can potentiate the activity of antibiotics against drug-resistant E. coli. Time-kill studies reported that a combination of DPM and erythromycin exhibited greater inhibitory activity against drug-resistant Escherichia coli. Dye accumulation and dye efflux studies using Hoechst 33342 and ethidium bromide showed that the addition of DPM significantly increased dye accumulation and reduced dye efflux in drug-resistant E. coli, suggesting its interference with dye translocation by an efflux pump. Using MALDI-TOF, it was observed that the addition of DPM could continuously reduce antibiotic efflux in drug-resistant E. coli. Additionally, DPM did not seem to damage the E. coli membranes, and the cell toxicity test showed that it features mild human-cell toxicity. In conclusion, these findings showed that DPM could serve as a potential EPI for drug-resistant E. coli.

scholarly journals The Evolutionary Conservation of Escherichia coli Drug Efflux Pumps Supports Physiological Functions

2020 ◽  
Vol 202 (22) ◽  
Author(s):  
Tanisha Teelucksingh ◽  
Laura K. Thompson ◽  
Georgina Cox
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Evolutionary Conservation ◽  
Drug Efflux ◽  
Physiological Functions ◽  
Content Type ◽  
Bacterial Physiology ◽  
E Coli ◽  
Drug Efflux Pumps

ABSTRACT Bacteria harness an impressive repertoire of resistance mechanisms to evade the inhibitory action of antibiotics. One such mechanism involves efflux pump-mediated extrusion of drugs from the bacterial cell, which significantly contributes to multidrug resistance. Intriguingly, most drug efflux pumps are chromosomally encoded components of the intrinsic antibiotic resistome. In addition, in terms of xenobiotic detoxification, bacterial efflux systems often exhibit significant levels of functional redundancy. Efflux pumps are also considered to be highly conserved; however, the extent of conservation in many bacterial species has not been reported and the majority of genes that encode efflux pumps appear to be dispensable for growth. These observations, in combination with an increasing body of experimental evidence, imply alternative roles in bacterial physiology. Indeed, the ability of efflux pumps to facilitate antibiotic resistance could be a fortuitous by-product of ancient physiological functions. Using Escherichia coli as a model organism, we here evaluated the evolutionary conservation of drug efflux pumps and we provide phylogenetic analysis of the major efflux families. We show the E. coli drug efflux system has remained relatively stable and the majority (∼80%) of pumps are encoded in the core genome. This analysis further supports the importance of drug efflux pumps in E. coli physiology. In this review, we also provide an update on the roles of drug efflux pumps in the detoxification of endogenously synthesized substrates and pH homeostasis. Overall, gaining insight into drug efflux pump conservation, common evolutionary ancestors, and physiological functions could enable strategies to combat these intrinsic and ancient elements.

Copper nanoparticles as an efflux pump inhibitor to tackle drug resistant bacteria

RSC Advances ◽  
2015 ◽  
Vol 5 (17) ◽  
pp. 12899-12909 ◽  
Author(s):  
Lowrence Rene Christena ◽  
Vimalanathan Mangalagowri ◽  
Prabhakaran Pradheeba ◽  
Khan Behlol Ayaz Ahmed ◽  
Bastin Infanta Sandhiya Shalini ◽  
...  
Keyword(s):  
Copper Nanoparticles ◽  
Efflux Pump ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Efflux Pump Inhibitor ◽  
Drug Resistant Bacteria

Casein capped copper nanoparticles at sub inhibitory concentrations function as an efflux pump inhibitor and restores susceptibility to antibiotics in drug resistant bacteria.

scholarly journals Whole genome sequences of multi-drug resistant Escherichia coli isolated in a Pastoralist Community of Western Uganda: Phylogenomic changes, virulence and resistant genes

2020 ◽  
Author(s):  
Jacob Stanley Iramiot ◽  
Henry Kajumbula ◽  
Joel Bazira ◽  
Etienne P. de Villiers ◽  
Benon B. Asiimwe
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Whole Genome ◽  
Beta Lactamase ◽  
Drug Resistant ◽  
Genome Sequences ◽  
E Coli ◽  
Resistant Genes ◽  
Pastoralist Community ◽  
Western Uganda

AbstractBackgroundThe crisis of antimicrobial resistance is already here with us, affecting both humans and animals alike and very soon, small cuts and surgeries will become life threatening. This study aimed at determine the whole genome sequences of multi-drug resistant Escherichia coli isolated in a Pastoralist Community of Western Uganda: phylogenomic changes, virulence and resistant genes.MethodsThis was a laboratory based cross sectional study. Bacterial isolates analyzed in this study were 42 multidrug resistant E. coli isolated from stool samples from both humans and cattle in pastoralist communities collected between January 2018-March 2019. Most of the isolates (41/42) were resistant to three or more antibiotics (multi-drug resistant) and 21/42 isolates were ESBL producers; 13/42 from human and 8/42 from cattle. Whole Genome Sequencing (WGS) was carried out at the facilities of Kenya Medical Research Institute-Wellcome trust, Kilifi, to determine the phylogenomic changes, virulence and resistant genes.ResultsThe genomes of the human E. coli generally clustered together and away from those of cattle origin. The E. coli isolates were assigned to eight different phylogroups: A, B1, B2, Cladel, D, E, F and G, with a majority being assigned to phylogroup A; while most of the animal isolates were assigned to phylogroup B1. The carriage of multiple AMR genes was higher from the E. coli population from humans than those from cattle. Among these were Beta-lactamase; blaOXA-1: Class D beta-lactamases; blaTEM-1, blaTEM-235: Beta-lactamase; catA1: chloramphenicol acetyl transferase; cmlA1: chloramphenicol efflux transporter; dfrA1, dfrA12, dfrA14, dfrA15, dfrA17, dfrA5, dfrA7, dfrA8: macrolide phosphotransferase; oqxB11: RND efflux pump conferring resistance to fluoroquinolone; qacL, qacEdelta1: quinolone efflux pump; qnrS1: quinolone resistance gene; sul1, sul2, sul3: sulfonamide resistant; tet(A), tet(B): tetracycline efflux pump.A high variation of virulence genes was registered among the E. coli genomes from humans than those of cattle origin.ConclusionThe E. coli of human and cattle origin are largely independent with different ancestral origins. Limited sharing of strains and resistance genes presents a challenge to the hypothesis that AMR in humans is as a result of antibiotic misuse on the farm.

scholarly journals Risk factors for fecal carriage of multidrug-resistant Escherichia coli in a college community: a penalized regression model

2020 ◽  
Author(s):  
Yuan Hu ◽  
Julia Rubin ◽  
Kaitlyn Mussio ◽  
Lee W. Riley
Keyword(s):  
Risk Factors ◽  
Escherichia Coli ◽  
Logistic Regression ◽  
Penalized Regression ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
E Coli ◽  
College Community ◽  
Fecal Carriage

AbstractBackgroundBacterial antimicrobial resistance is a serious global public health threat. Intestinal commensal drug-resistant bacteria have been suggested as an important reservoir of antimicrobial resistant genes (ARGs), which may be acquired via food. We aimed to identify risk factors associated with fecal carriage of drug-resistant commensal Escherichia coli (E. coli) among healthy adults focused on their dietary habit.MethodsWe conducted a cross-sectional study targeting healthy adult volunteers in a college community. Fecal samples and questionnaires were obtained from 113 volunteers. We conducted backward elimination logistic regression and least absolute shrinkage and selection (LASSO) methods to identify risk factors.ResultsWe analyzed responses from 81 of 113 volunteers who completed the questionnaire. The logistic regression and LASSO methods identified red meat consumption to be associated with increased risk (OR = 6.13 [1.83-24.2] and 1.82, respectively) and fish consumption with reduced risk (OR = 0.27 [0.08-0.85] and 0.82) for the carriage of multidrug-resistant E. coli, adjusted for gender, employment status, frequently-used supermarket, and previous travel.ConclusionsDietary habits are associated with the risk of fecal carriage of multidrug-resistant E. coli. This study supports the growing evidence that food may be an important source of ARGs present in human commensal E. coli.

scholarly journals Photodynamic Inactivation of Bacteria with Porphyrin Derivatives: Effect of Charge, Lipophilicity, ROS Generation, and Cellular Uptake on Their Biological Activity In Vitro

2020 ◽  
Vol 21 (22) ◽  
pp. 8716
Author(s):  
Adam Sułek ◽  
Barbara Pucelik ◽  
Marcin Kobielusz ◽  
Agata Barzowska ◽  
Janusz M. Dąbrowski
Keyword(s):  
Cellular Uptake ◽  
Efflux Pump ◽  
Theoretical Calculations ◽  
Resistant Bacteria ◽  
Ros Generation ◽  
Photodynamic Inactivation ◽  
Efflux Pump Inhibitor ◽  
E Coli ◽  
Charge Interaction

Resistance of microorganisms to antibiotics has led to research on various therapeutic strategies with different mechanisms of action, including photodynamic inactivation (PDI). In this work, we evaluated a cationic, neutral, and anionic meso-tetraphenylporphyrin derivative’s ability to inactivate the Gram-negative and Gram-positive bacteria in a planktonic suspension under blue light irradiation. The spectroscopic, physicochemical, redox properties, as well as reactive oxygen species (ROS) generation capacity by a set of photosensitizers varying in lipophilicity were investigated. The theoretical calculations were performed to explain the distribution of the molecular charges in the evaluated compounds. Moreover, logP partition coefficients, cellular uptake, and phototoxicity of the photosensitizers towards bacteria were determined. The role of a specific microbial efflux pump inhibitor, verapamil hydrochloride, in PDI was also studied. The results showed that E. coli exhibited higher resistance to PDI than S. aureus (3–5 logs) with low light doses (1–10 J/cm2). In turn, the prolongation of irradiation (up to 100 J/cm2) remarkably improved the inactivation of pathogens (up to 7 logs) and revealed the importance of photosensitizer photostability. The PDI potentiation occurs after the addition of KI (more than 3 logs extra killing). Verapamil increased the uptake of photosensitizers (especially in E. coli) due to efflux pump inhibition. This effect suggests that PDI is mediated by ROS, the electrostatic charge interaction, and the efflux of photosensitizers (PSs) regulated by multidrug-resistance (MDR) systems. Thus, MDR inhibition combined with PDI gives opportunities to treat more resistant bacteria.

scholarly journals Effects of Chlorophyll-Derived Efflux Pump Inhibitor Pheophorbide a and Pyropheophorbide a on Growth and Macrolide Antibiotic Resistance of Indicator and Anaerobic Swine Manure Bacteria

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Mareike Kraatz ◽  
Terence R. Whitehead ◽  
Michael A. Cotta ◽  
Mark A. Berhow ◽  
Mark A. Rasmussen
Keyword(s):  
Bacterial Resistance ◽  
Efflux Pump ◽  
Growth Parameters ◽  
Swine Manure ◽  
Efflux Pumps ◽  
Resistant Bacteria ◽  
Pheophorbide A ◽  
Efflux Pump Inhibitor ◽  
E Coli ◽  
Pyropheophorbide A

Natural plant compounds, such as the chlorophyll a catabolites pheophorbide a (php) and pyropheophorbide a (pyp), are potentially active in the gastrointestinal tracts and manure of livestock as antimicrobial resistance-modifying agents through inhibition of bacterial efflux pumps. To investigate whether php, a known efflux pump inhibitor, and pyp influence bacterial resistance, we determined their long-term effects on the MICs of erythromycin for reference strains of clinically relevant indicator bacteria with macrolide or multidrug resistance efflux pumps. Pyp reduced the final MIC endpoint for Staphylococcus (S.) aureus and Escherichia (E.) coli by up to 1536 and 1024 μg erythromycin mL−1 or 1.4- and 1.2-fold, respectively. Estimation of growth parameters of S. aureus revealed that pyp exerted an intrinsic inhibitory effect under anaerobic conditions and was synergistically active, thereby potentiating the effect of erythromycin and partially reversing high-level erythromycin resistance. Anaerobe colony counts of total and erythromycin-resistant bacteria from stored swine manure samples tended to be lower in the presence of pyp. Tylosin, php, and pyp were not detectable by HPLC in the manure or medium. This is the first study showing that pyp affects growth and the level of sensitivity to erythromycin of S. aureus, E. coli, and anaerobic manure bacteria.

scholarly journals 1-benzyl-1,4-diazepane reduces the efflux of resistance-nodulation-cell division pumps in Escherichia coli

2020 ◽  
Vol 15 (11) ◽  
pp. 987-999
Author(s):  
Enrico Casalone ◽  
Tiziano Vignolini ◽  
Laura Braconi ◽  
Lucia Gardini ◽  
Marco Capitanio ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Ethidium Bromide ◽  
Inhibitory Concentration ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Efflux Pump Inhibitor ◽  
E Coli ◽  
Microdilution Method ◽  
Photoactivated Localization Microscopy ◽  
Mixed Mechanism

Aim: To investigate the action mechanism of 1-benzyl-1,4-diazepane (1-BD) as efflux pump inhibitor (EPI) in Escherichia coli mutants: Δ acrAB or overexpressing AcrAB and AcrEF efflux pumps. Materials & methods: Effect of 1-BD on: antibiotic potentiation, by microdilution method; membrane functionality, by fluorimetric assays; ethidium bromide accumulation, by fluorometric real-time efflux assay; AcrB expression, by quantitative photoactivated localization microscopy. Results: 1-BD decreases the minimal inhibitory concentration of levofloxacin and other antibiotics and increase ethidium bromide accumulation in E. coli overexpressing efflux pumps but not in the Δ acrAB strain. 1-BD increases membranes permeability, without sensibly affecting inner membrane polarity and decreases acrAB transcription. Conclusion: 1-BD acts as an EPI in E. coli with a mixed mechanism, different from that of major reference EPIs.

scholarly journals Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant Escherichia coli

2020 ◽  
Vol 21 (23) ◽  
pp. 9134
Author(s):  
Ilaria Passarini ◽  
Pedro Ernesto de Resende ◽  
Sarah Soares ◽  
Tadeh Tahmasi ◽  
Paul Stapleton ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
In Silico ◽  
Mammalian Cells ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Coli Strain ◽  
Cell Permeability ◽  
Cationic Peptides ◽  
Drug Resistant ◽  
E Coli

Cationic antimicrobial peptides have attracted interest, both as antimicrobial agents and for their ability to increase cell permeability to potentiate other antibiotics. However, toxicity to mammalian cells and complexity have hindered development for clinical use. We present the design and synthesis of very short cationic peptides (3–9 residues) with potential dual bacterial membrane permeation and efflux pump inhibition functionality. Peptides were designed based upon in silico similarity to known active peptides and efflux pump inhibitors. A number of these peptides potentiate the activity of the antibiotic novobiocin against susceptible Escherichia coli and restore antibiotic activity against a multi-drug resistant E. coli strain, despite having minimal or no intrinsic antimicrobial activity. Molecular modelling studies, via docking studies and short molecular dynamics simulations, indicate two potential mechanisms of potentiating activity; increasing antibiotic cell permeation via complexation with novobiocin to enable self-promoted uptake, and binding the E. coli RND efflux pump. These peptides demonstrate potential for restoring the activity of hydrophobic drugs.

scholarly journals Synthesis and Study of New Quinolineaminoethanols as Anti-Bacterial Drugs

2019 ◽  
Vol 12 (2) ◽  
pp. 91
Author(s):  
Laumaillé ◽  
Dassonville-Klimpt ◽  
Peltier ◽  
Mullié ◽  
Andréjak ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
E Coli ◽  
Gram Positive Bacteria ◽  
Drug Resistant Bacteria ◽  
Escherichia Coli Bacteria

The lack of antibiotics with a novel mode of action associated with the spread of drug resistant bacteria make the fight against infectious diseases particularly challenging. A quinoline core is found in several anti-infectious drugs, such as mefloquine and bedaquiline. Two main objectives were set in this work. Firstly, we evaluated the anti-mycobacterial properties of the previous quinolines 3, which have been identified as good candidates against ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli) bacteria. Secondly, a new series 4 was designed and assessed against the same bacteria strains, taking the pair of enantiomers 3m/3n as the lead. More than twenty compounds 4 were prepared through a five-step asymmetric synthesis with good enantiomeric excesses (>90%). Interestingly, all compounds of series 3 were efficient on M. avium with MIC = 2–16 µg/mL, while series 4 was less active. Both series 3 and 4 were generally more active than mefloquine against the ESKAPEE bacteria. The quinolines 4 were either active against Gram-positive bacteria (MIC ≤ 4 µg/mL for 4c–4h and 4k/4l) or E. coli (MIC = 32–64 µg/mL for 4q–4v) according to the global lipophilicity of these compounds.

Human glucose-dependent insulinotropic polypeptide (GIP) is an antimicrobial adjuvant re-sensitising multidrug-resistant Gram-negative bacteria

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Da’san M. M. Jaradat ◽  
Nehaya Al-Karablieh ◽  
Basmah H. M. Zaarer ◽  
Wenyi Li ◽  
Khalil K.Y. Saleh ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
E Coli ◽  
Low Concentrations ◽  
Bacterial Mutants ◽  
Drug Efflux Pumps ◽  
Gastrointestinal Peptides

Abstract Increasing antibiotic resistance in Gram-negative bacteria has mandated the development of both novel antibiotics and alternative therapeutic strategies. Evidence of interplay between several gastrointestinal peptides and the gut microbiota led us to investigate potential and broad-spectrum roles for the incretin hormone, human glucose-dependent insulinotropic polypeptide (GIP) against the Enterobacteriaceae bacteria, Escherichia coli and Erwinia amylovora. GIP had a potent disruptive action on drug efflux pumps of the multidrug resistant bacteria E. coli TG1 and E. amylovora 1189 strains. The effect was comparable to bacterial mutants lacking the inner and outer membrane efflux pump factor proteins AcrB and TolC. While GIP was devoid of direct antimicrobial activity, it has a potent membrane depolarizing effect, and at low concentrations, it significantly potentiated the activity of eight antibiotics and bile salt by reducing MICs by 4-8-fold in E. coli TG1 and 4-20-fold in E. amylovora 1189. GIP can thus be regarded as an antimicrobial adjuvant with potential for augmenting the available antibiotic arsenal.

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