scholarly journals Resurrecting the Dead: Mitigating Efflux-Pump Inhibitor Toxicity using a Liposomal Delivery System to Recover Efficacy of Antimicrobial Drugs

2021 ◽  
Vol 5 (9) ◽  
pp. 1-7
Author(s):  
Prachi Ray ◽  
Kha Nguyen ◽  
Truong Nguyen ◽  
Sukriti Sachdev
Keyword(s):  
Delivery System ◽  
Efflux Pump ◽  
Efflux Pump Inhibitor ◽  
Antimicrobial Drugs ◽  
Liposomal Delivery ◽  
The Dead

scholarly journals The Impact of an Efflux Pump Inhibitor on the Activity of Free and Liposomal Antibiotics against Pseudomonas aeruginosa

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 577
Author(s):  
Douweh Leyla Gbian ◽  
Abdelwahab Omri
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Antimicrobial Activities ◽  
Dilution Method ◽  
Efflux Pump Inhibitor ◽  
Signal Production ◽  
Lung Infections ◽  
The Impact ◽  
Microbroth Dilution

The eradication of Pseudomonas aeruginosa in cystic fibrosis patients has become continuously difficult due to its increased resistance to treatments. This study assessed the efficacy of free and liposomal gentamicin and erythromycin, combined with Phenylalanine arginine beta-naphthylamide (PABN), a broad-spectrum efflux pump inhibitor, against P. aeruginosa isolates. Liposomes were prepared and characterized for their sizes and encapsulation efficiencies. The antimicrobial activities of formulations were determined by the microbroth dilution method. Their activity on P. aeruginosa biofilms was assessed, and the effect of sub-inhibitory concentrations on bacterial virulence factors, quorum sensing (QS) signals and bacterial motility was also evaluated. The average diameters of liposomes were 562.67 ± 33.74 nm for gentamicin and 3086.35 ± 553.95 nm for erythromycin, with encapsulation efficiencies of 13.89 ± 1.54% and 51.58 ± 2.84%, respectively. Liposomes and PABN combinations potentiated antibiotics by reducing minimum inhibitory and bactericidal concentrations by 4–32 fold overall. The formulations significantly inhibited biofilm formation and differentially attenuated virulence factor production as well as motility. Unexpectedly, QS signal production was not affected by treatments. Taken together, the results indicate that PABN shows potential as an adjuvant of liposomal macrolides and aminoglycosides in the management of lung infections in cystic fibrosis patients.

Automated graves: The precarity and prosthetics of caring for the dead in Japan

2021 ◽  
Vol 24 (4) ◽  
pp. 622-636
Author(s):  
Anne Allison
Keyword(s):  
Delivery System ◽  
Aging Population ◽  
Just In Time ◽  
Human Relations ◽  
Ethnographic Fieldwork ◽  
The Dead ◽  
The Temple

Once dependent on family to bury and memorialize the dead, caring for the deceased has become increasingly precarious in the wake of a decreasing and aging population, a trend towards single households, and downsizing of social relationality—including the temple parishioner system once key in mortuary rituals. In the new “ending” marketplace emerging today to help Japanese manage this precarity, automated graves offer customers a convenient burial spot in an urban ossuary where ashes, interred in a deposit box, are automatically transferred to a grave upon visitation. Based on ethnographic fieldwork, the article examines the just-in-time delivery system at work in automated graves, arguing that the mechanism serves as a social prosthesis, propping up the allure of social caring for the dead, even for those whose ashes are never visited by human relations. With over 30 such institutions now operating in Japan, automated graves are a sign of changing sociality between the living and the dead.

scholarly journals Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity

2018 ◽  
Vol Volume 13 ◽  
pp. 763-776 ◽  
Author(s):  
Xiao-qian Dou ◽  
Hua Wang ◽  
Jing Zhang ◽  
Fang Wang ◽  
Gui-li Xu ◽  
...  
Keyword(s):  
Delivery System ◽  
Targeted Delivery ◽  
Drug Conjugate ◽  
Liposomal Delivery

scholarly journals Staphylococcus aureus Mutants Isolated via Exposure to Nonfluorinated Quinolones: Detection of Known and Unique Mutations

2001 ◽  
Vol 45 (12) ◽  
pp. 3422-3426 ◽  
Author(s):  
Siddhartha Roychoudhury ◽  
Tracy L. Twinem ◽  
Kelly M. Makin ◽  
Mark A. Nienaber ◽  
Chuiying Li ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Sequence Analysis ◽  
Efflux Pump ◽  
Serial Passage ◽  
Efflux Pump Inhibitor ◽  
In Vitro Development ◽  
Development Of Resistance ◽  
High Level ◽  
Vitro Development

ABSTRACT The in vitro development of resistance to the new nonfluorinated quinolones (NFQs; PGE 9262932, PGE 4175997, and PGE 9509924) was investigated in Staphylococcus aureus. At concentrations two times the MIC, step 1 mutants were isolated more frequently with ciprofloxacin and trovafloxacin (9.1 × 10−8 and 5.7 × 10−9, respectively) than with the NFQs, gatifloxacin, or clinafloxacin (<5.7 × 10−10). Step 2 and step 3 mutants were selected via exposure of a step 1 mutant (selected with trovafloxacin) to four times the MICs of trovafloxacin and PGE 9262932. The step 1 mutant contained the known Ser80-Phe mutation in GrlA, and the step 2 and step 3 mutants contained the known Ser80-Phe and Ser84-Leu mutations in GrlA and GyrA, respectively. Compared to ciprofloxacin, the NFQs were 8-fold more potent against the parent and 16- to 128-fold more potent against the step 3 mutants. Mutants with high-level NFQ resistance (MIC, 32 μg/ml) were isolated by the spiral plater-based serial passage technique. DNA sequence analysis of three such mutants revealed the following mutations: (i) Ser84-Leu in GyrA and Glu84-Lys and His103-Tyr in GrlA; (ii) Ser-84Leu in GyrA, Ser52-Arg in GrlA, and Glu472-Val in GrlB; and (iii) Ser84-Leu in GyrA, Glu477-Val in GyrB, and Glu84-Lys and His103-Tyr in GrlA. Addition of the efflux pump inhibitor reserpine (10 μg/ml) resulted in 4- to 16-fold increases in the potencies of the NFQs against these mutants, whereas it resulted in 2-fold increases in the potencies of the NFQs against the parent.

Multivesicular liposome: A lipid-based drug delivery system for efficient drug delivery

2021 ◽  
Vol 27 ◽  
Author(s):  
Bapi Gorain ◽  
Bandar E. Al-Dhubiab ◽  
Anroop Nair ◽  
Prashant Kesharwani ◽  
Manisha Pandey ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Sustained Release ◽  
Delivery System ◽  
Targeted Delivery ◽  
Drug Loading ◽  
Therapeutic Agents ◽  
Laboratory Research ◽  
Efficacy And Safety ◽  
Liposomal Delivery ◽  
Proteins And Peptides

: The advancement of delivery tools for therapeutic agents has brought several novel formulations with increased drug loading, sustained release, targeted delivery, and prolonged efficacy. Amongst the several novel delivery approaches, multivesicular liposome has gained potential interest because this delivery system possesses the above advantages. In addition, this multivesicular liposomal delivery prevents degradation of the entrapped drug within the physiological environment while administered. The special structure of the vesicles allowed successful entrapment of hydrophobic and hydrophilic therapeutic agents, including proteins and peptides. Furthermore, this novel formulation could maintain the desired drug concentration in the plasma for a prolonged period, which helps to reduce the dosing frequencies, improve bioavailability, and safety. This tool could also provide stability of the formulation, and finally gaining patient compliance. Several multivesicular liposomes received approval for clinical research, while others are at different stages of laboratory research. In this review, we have focused on the preparation of multivesicular liposomes along with their application in different ailments for the improvement of the performance of the entrapped drug. Moreover, the challenges of delivering multivesicular vesicles have also been emphasized. Overall, it could be inferred that multivesicular liposomal delivery is a novel platform of advanced drug delivery with improved efficacy and safety.

EXTH-31. BRAIN DISTRIBUTION, CLEARANCE AND TOXICITY EVALUATION OF SMALL-MOLECULE INHIBITORS FOLLOWING CONVECTION-ENHANCED DELIVERY TO THE BRAINSTEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi170-vi170
Author(s):  
Erica Power ◽  
Juhee Oh ◽  
Jonghoon Choi ◽  
William Elmquist ◽  
David Daniels
Keyword(s):  
Small Molecule ◽  
Drug Concentration ◽  
Small Molecule Inhibitors ◽  
Efflux Pump ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Efflux Pump Inhibitor ◽  
Delivery Technique ◽  
The Brain

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials. OBJECTIVE The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem. METHODS Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis. RESULTS No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor. CONCLUSIONS These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.

scholarly journals Target (MexB)- and Efflux-Based Mechanisms Decreasing the Effectiveness of the Efflux Pump Inhibitor D13-9001 in Pseudomonas aeruginosa PAO1: Uncovering a New Role for MexMN-OprM in Efflux of β-Lactams and a Novel Regulatory Circuit (MmnRS) Controlling MexMN Expression

2018 ◽  
Vol 63 (2) ◽  
pp. e01718-18 ◽  
Author(s):  
Srijan Ranjitkar ◽  
Adriana K. Jones ◽  
Mina Mostafavi ◽  
Zachary Zwirko ◽  
Oleg Iartchouk ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Response Regulator ◽  
Heavy Metal Resistance ◽  
Metal Resistance ◽  
Rna Seq ◽  
Efflux Pump Inhibitor ◽  
Content Type ◽  
Regulatory Circuit ◽  
Outer Membrane Channel

ABSTRACT Efflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance. D13-9001 specifically inhibits MexAB-OprM in Pseudomonas aeruginosa. Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified, and these fell into two categories: those with alterations in the target MexB (F628L and ΔV177) and those with an alteration in a putative sensor kinase of unknown function, PA1438 (L172P). The alterations in MexB were consistent with reported structural studies of the D13-9001 interaction with MexB. The PA1438L172P alteration mediated a >150-fold upregulation of MexMN pump gene expression and a >50-fold upregulation of PA1438 and the neighboring response regulator gene, PA1437. We propose that these be renamed mmnR and mmnS for MexMN regulator and MexMN sensor, respectively. MexMN was shown to partner with the outer membrane channel protein OprM and to pump several β-lactams, monobactams, and tazobactam. Upregulated MexMN functionally replaced MexAB-OprM to efflux these compounds but was insusceptible to inhibition by D13-9001. MmnSL172P also mediated a decrease in susceptibility to imipenem and biapenem that was independent of MexMN-OprM. Expression of oprD, encoding the uptake channel for these compounds, was downregulated, suggesting that this channel is also part of the MmnSR regulon. Transcriptome sequencing (RNA-seq) of cells encoding MmnSL172P revealed, among other things, an interrelationship between the regulation of mexMN and genes involved in heavy metal resistance.

scholarly journals PUNICA GRANATUM RIND EXTRACT: ANTIBIOTIC POTENTIATOR AND EFFLUX PUMP INHIBITOR OF MULTIDRUG RESISTANT KLEBSIELLA PNEUMONIAE CLINICAL ISOLATES

2017 ◽  
Vol 10 (3) ◽  
pp. 191 ◽  
Author(s):  
Zumaana Rafiq ◽  
Sreevidya Narasimhan ◽  
Magesh Haridoss ◽  
Rosy Vennila ◽  
Rama Vaidyanathan
Keyword(s):  
Klebsiella Pneumoniae ◽  
Efflux Pump ◽  
Ethanol Extract ◽  
Punica Granatum ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Sequential Fractionation ◽  
Efflux Pump Inhibitor ◽  
Fold Reduction ◽  
Significant Area

ABSTRACTObjective: With a rise in multidrug resistant (MDR) bacterial isolates, search for antibiotics or compounds that could act synergistically with themis a significant area of research. Efflux-mediated resistance, in particular, is a great hurdle that needs to be overcome. In an effort to identify suchsynergistic compounds and potential efflux pump inhibitors (EPI), we analyzed the rind of Punica granatum (pomegranate) against MDR clinicalKlebsiella pneumoniae isolates.Methods: Sequential fractionation of P. granatum rind ethanol (PGR) extract was carried out to obtain hexane, butanol and water fractions.Antibacterial activity of the plant extracts was confirmed, and synergistic interaction with antibiotics was determined by the checkerboard assay. Gaschromatography-mass spectrometry (GC-MS) analysis was performed to identify the phytochemical constituents of the hexane extract. To study EPIactivity of the extracts, norfloxacin accumulation assay was carried out.Results: PGR ethanol extract was found to have synergistic activity with ciprofloxacin, levofloxacin, ceftazidime, cefoxitin, meropenem, and gentamicinresulting in fold decrease of minimum inhibitory concentration (MIC) ranging from 2 to 32 fold. The hexane fraction was found to have maximumsynergistic activity resulting in a 32-fold reduction of ciprofloxacin MIC followed by butanol and water fractions. The PGR ethanol extract was alsofound to have efflux inhibition activity by the norfloxacin accumulation assay. Of the sequential fractions, the butanol fraction had maximum effluxinhibition activity.Conclusion: Therefore, our study shows that PGR extract can potentiate the effect of antibiotics on MDR bacteria, and the mode of action is likely tobe due to EPI.Keywords: Punica granatum rind, Pomegranate, Synergy with antibiotics, Multidrug resistant, Klebsiella pneumoniae, Efflux pump inhibition.

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