Read by QxMD icon Read

efflux pump inhibition

Narges Abdali, Jerry Matthew Parks, Keith Haynes, Julie L Chaney, Adam T Green, David Wolloscheck, John K Walker, Valentin V Rybenkov, Jerome Yves Baudry, Jeremy C Smith, Helen I Zgurskaya
Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for development of effective EPIs, especially in light of constantly emerging resistance. Here, we describe EPIs that interact with periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel...
October 21, 2016: ACS Infectious Diseases
Sandrine Alibert, Joannah N'Gompazza Diarra, Jessica Hernandez, Aurélien Stutzmann, Marwa Fouad, Gérard Boyer, Jean-Marie Pagès
Worrying levels of bacterial resistance have been reported worldwide involving the failure of many available antibiotic treatments. Multidrug resistance (MDR) in Gram-negative bacteria is often ascribed to the presence of multiple and different resistance mechanisms in the same strain. RND efflux pumps play a major role and are an attractive target to discover new antibacterial drugs. Areas covered: This review discusses the prevalence of efflux pumps, their overexpression in clinical scenarios, their polyselectivity, their effect on the intracellular concentrations of various antibiotics associated with the alteration of the membrane permeability and their involvement in pathogenicity are discussed...
October 20, 2016: Expert Opinion on Drug Metabolism & Toxicology
Jinshan Jin, Ying-Hsin Hsieh, Jianmei Cui, Krishna Damera, Chaofeng Dai, Arpana S Chaudhary, Hao Zhang, Hsiuchin Yang, Nannan Cao, Chun Jiang, Martti Vaara, Binghe Wang, Phang C Tai
With the widespread emergence of drug resistance, there is an urgent need to search for new antimicrobials, especially those against Gram-negative bacteria. Along this line, the identification of viable targets is a critical first step. The protein translocase SecA is commonly believed to be an excellent target for the development of broad-spectrum antimicrobials. In recent years, we developed three structural classes of SecA inhibitors that have proven to be very effective against Gram-positive bacteria. However, we have not achieved the same level of success against Gram-negative bacteria, despite the potent inhibition of SecA in enzyme assays by the same inhibitors...
October 18, 2016: ChemMedChem
Bożena Karolewicz
In the article, groups of multifunctional polymers used in drug dosage form technology were classified and evaluated. These compounds, in addition to their basic function as excipients, may have additional properties, e.g. stimuli sensitivity, enzyme inhibition, intestinal epithelium penetration enhancement, efflux pump inhibition, taste-masking, pharmacological activity and the ability to interact with enzymes responsible for drug metabolism. While classifying specific groups of multifunctional polymers, special emphasis was placed on the advantages of using them when designing new drug...
September 2016: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Malkeet Kumar, Kawaljit Singh, Krupa Naran, Fahreta Hamzabegovic, Daniel F Hoft, Digby F Warner, Peter Ruminski, Getahun Abate, Kelly Chibale
Efflux pumps are considered a major potential contributor to the development of various forms of resistance in Mycobacterium tuberculosis leading to the emergence of multidrug-resistant tuberculosis (TB). Verapamil (VER) and tricyclic chemosensitizers such as the phenothiazines are known to possess efflux pump inhibition properties and have demonstrated significant efficacy in various TB disease models. Novel hybrid molecules based on fusion of the VER substructure with various tricyclic, as well as nontricyclic, chemosensitizer cores or their structural motifs are described...
October 14, 2016: ACS Infectious Diseases
Wanida Phetsang, Ruby Pelingon, Mark S Butler, Sanjaya Kc, Miranda E Pitt, Geraldine Kaeslin, Matthew A Cooper, Mark A T Blaskovich
Reduced susceptibility to antimicrobials in Gram-negative bacteria may result from multiple resistance mechanisms, including increased efflux pump activity or reduced porin protein expression. Up-regulation of the efflux pump system is closely associated with multidrug resistance (MDR). To help investigate the role of efflux pumps on compound accumulation, a fluorescence-based assay was developed using fluorescent derivatives of trimethoprim (TMP), a broad-spectrum synthetic antibiotic that inhibits an intracellular target, dihydrofolate reductase (DHFR)...
October 14, 2016: ACS Infectious Diseases
A Klančnik, M Šikić Pogačar, K Trošt, M Tušek Žnidarič, B Mozetič Vodopivec, S Smole Možina
AIMS: To define anti-Campylobacter jejuni activity of an extract from waste skins and seeds of Pinot noir grapes (GSS) and of resveratrol, and possible resistance mechanisms, and the influence of these on C. jejuni morphology. METHODS AND RESULTS: Using gene-specific knock-out C. jejuni mutants and an efflux-pump inhibitor, we show CmeABC as the most active efflux pump for extrusion across the outer membrane of GSS extract and resveratrol. Using polystyrene and pig small-intestine epithelial (PSI) and human foetal small intestine (H4) cell lines, GSS extract shows efficient inhibition of adhesion of C...
October 6, 2016: Journal of Applied Microbiology
Max R Schroeder, David S Stephens
Streptococcus pneumoniae is a common commensal and an opportunistic pathogen. Suspected pneumococcal upper respiratory infections and pneumonia are often treated with macrolide antibiotics. Macrolides are bacteriostatic antibiotics and inhibit protein synthesis by binding to the 50S ribosomal subunit. The widespread use of macrolides is associated with increased macrolide resistance in S. pneumoniae, and the treatment of pneumococcal infections with macrolides may be associated with clinical failures. In S...
2016: Frontiers in Cellular and Infection Microbiology
Adam M Speen, Hye-Young H Kim, Rebecca N Bauer, Megan Meyer, Kymberly M Gowdy, Michael B Fessler, Kelly E Duncan, Wei Liu, Ned A Porter, Ilona Jaspers
When inhaled, ozone (O3) interacts with cholesterols of airway epithelial cell membranes or the lung lining fluid, generating chemically reactive oxysterols. The mechanism by which O3-derived oxysterols affect molecular function is unknown. Our data show that in vitro exposure of human bronchial epithelial cells to O3 results in the formation of oxysterols, epoxycholesterol-α and β (α-EpCh, β-EpCh) and Secosterol A and B (Seco A, SecoB), in cell lysates and apical washes. Similarly, bronchoalveolar lavage fluid obtained from human volunteers exposed to O3 contained elevated levels of these oxysterol species...
October 4, 2016: Journal of Biological Chemistry
Nopphasul Sirijant, Rasana W Sermswan, Surasakdi Wongratanacheewin
Burkholderia pseudomallei, the causative agent of melioidosis, has been found to increase its resistance to antibiotics when growing as a biofilm. The resistances are related to several mechanisms. One of the possible mechanisms is the efflux pump. Using bioinformatics analysis, it was found that BPSL1661, BPSL1664 and BPSL1665 were orthologous genes of the efflux transporter encoding genes for biofilm related antibiotic resistance PA1874-PA1877 genes in Pseudomonas aeruginosa strain PAO1. Expressions of selected encoding genes for the efflux transporter system during biofilm formation were investigated...
September 30, 2016: Journal of Medical Microbiology
Ganesh Krishnamoorthy, David Wolloscheck, Jon W Weeks, Cameron Croft, Valentin V Rybenkov, Helen I Zgurskaya
In Gram-negative bacteria, a synergistic relationship between slow passive uptake of antibiotics across the outer membrane and active efflux transporters creates a permeability barrier, which efficiently reduces effective concentrations of antibiotics in cells and hence, their activities. To analyze the relative contributions of the active efflux and the passive barrier in activities of antibiotics, we constructed Escherichia coli strains with controllable permeability of the outer membrane. The strains express a large pore that does not discriminate compounds based on their hydrophilicity and sensitizes cells to a variety of antibacterial agents...
October 3, 2016: Antimicrobial Agents and Chemotherapy
T-D Ngo, T-D Tran, M-T Le, K-M Thai
The efflux pumps P-glycoprotein (P-gp) in humans and NorA in Staphylococcus aureus are of great interest for medicinal chemists because of their important roles in multidrug resistance (MDR). The high polyspecificity as well as the unavailability of high-resolution X-ray crystal structures of these transmembrane proteins lead us to combining ligand-based approaches, which in the case of this study were machine learning, perceptual mapping and pharmacophore modelling. For P-gp inhibitory activity, individual models were developed using different machine learning algorithms and subsequently combined into an ensemble model which showed a good discrimination between inhibitors and noninhibitors (acctrain-diverse = 84%; accinternal-test = 92% and accexternal-test = 100%)...
September 2016: SAR and QSAR in Environmental Research
Fei Xie, Wenqiang Chang, Ming Zhang, Ying Li, Wei Li, Hongzhuo Shi, Sha Zheng, Hongxiang Lou
One of the main azole-resistance mechanisms in Candida pathogens is the upregulation of drug efflux pumps, which compromises the efficacy of azoles and results in treatment failure. The combination of azole-antifungal agents with efflux pump inhibitors represents a promising strategy to combat fungal infection. High-throughput screening of 150 extracts obtained from endolichenic fungal cultures led to the discovery that the extract of Phialocephala fortinii exhibits potent activity for the reversal of azole resistance...
2016: Scientific Reports
Haoyu Sun, Hongming Ge, Min Zheng, Zhifen Lin, Ying Liu
Previous studies have identified a phenomenon in which the concentration-response curves (CRCs) for mixtures cross the curves for concentration addition model when predicting or judging joint toxic actions. However, mechanistic investigations of this phenomenon are extremely limited. In this study, a similar phenomenon was observed when we determined the joint toxic actions of sulfonamides (SAs) and erythromycin (ERY) on Escherichia coli (E. coli), which we named the "cross-phenomenon", and it was characterized by antagonism in the low-concentration range, addition in the medium-concentration range, and synergism in the high-concentration range...
2016: Scientific Reports
Ana Cristina Abreu, Maria José Saavedra, Lúcia C Simões, Manuel Simões
Combinations of selected phytochemicals (reserpine, pyrrolidine, quinine, morin and quercetin) with antibiotics (ciprofloxacin, tetracycline and erythromycin) were tested on the prevention and control of Staphylococcus aureus biofilms. The phytochemicals were also studied for their ability to avoid antibiotic adaptation and to inhibit antibiotic efflux pumps. Morin, pyrrolidine and quercetin at subinhibitory concentrations had significant effects in biofilm prevention and/or control when applied alone and combined with antibiotics...
October 2016: Biofouling
Felipe A Navarrete, Antonio Alvau, Hoi Chang Lee, Lonny R Levin, Jochen Buck, Patricia Martin-De Leon, Celia M Santi, Dario Krapf, Jesse Mager, Rafael A Fissore, Ana M Salicioni, Alberto Darszon, Pablo E Visconti
Mammalian sperm acquire fertilizing capacity in the female tract in a process called capacitation. At the molecular level, capacitation requires protein kinase A activation, changes in membrane potential and an increase in intracellular calcium. Inhibition of these pathways results in loss of fertilizing ability in vivo and in vitro. We demonstrated that transient incubation of mouse sperm with Ca(2+) ionophore accelerated capacitation and rescued fertilizing capacity in sperm with inactivated PKA function...
2016: Scientific Reports
Diana Machado, Rolando Cannalire, Sofia Santos Costa, Giuseppe Manfroni, Oriana Tabarrini, Violetta Cecchetti, Isabel Couto, Miguel Viveiros, Stefano Sabatini
The identification of efflux inhibitors to be used as adjuvants alongside existing drug regimens could have a tremendous value in the treatment of any mycobacterial infection. Here, we investigated the ability of four 2-(4'-propoxyphenyl)quinoline Staphylococcus aureus NorA efflux inhibitors (1-4) to reduce the efflux activity in Mycobacterium smegmatis and Mycobacterium avium strains. All four compounds were able to inhibit efflux pumps in both mycobacterial species; in particular, O-ethylpiperazinyl derivative 2 showed an efflux inhibitory activity comparable to that of verapamil, the most potent mycobacterial efflux inhibitor reported to date, and was able to significantly reduce the MIC values of macrolides against different M...
December 11, 2015: ACS Infectious Diseases
S Ghafourian
The main mechanism of quinolone resistance in K pneumoniae caused via mutation on porin-related proteins and efflux pumps. The current study aimed investigates the prevalence of ciprofloxacin resistant K pneumoniae in burn patients and understanding the role of AcrAB multidrug efflux system on minimal inhibitory concentration of ciprofloxacin. For this reason, 52 K pneumoniae collected from burn patients and evaluated for mechanism of ciprofloxacin resistance. The results demonstrated 40 K pneumoniae were ciprofloxacin resistant K pneumonia and 35 showed the mutation on gyrA...
March 10, 2016: West Indian Medical Journal
Ákos Csonka
INTRODUCTION: The reason for unsuccessful tumor chemotherapy is related to multidrug resistance. An important factor is the overexpression of efflux pumps, such as P-glycoprotein. AIM: Amino- and amide-substituted steroid compounds and phenothiazine derivatives were investigated in tumor models in vitro. METHOD: The inhibition of P-glycoprotein was evaluated by flow cytometry and the interaction of these compounds with doxorubicin was investigated as well...
September 2016: Orvosi Hetilap
Gabriela Rozic, Lena Paukov, Jana Jakubikova, Dikla Ben-Shushan, Adrian Duek, Adi Leiba, Abraham Avigdor, Arnon Nagler, Merav Leiba
Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy.STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This molecule had potent cytotoxic activity against several MM cell lines and patient-derived MM cells. Moreover, STK405759 demonstrated cytotoxicity against drug-resistant myeloma cells that overexpressed the P-glycoprotein drug-efflux pump...
August 23, 2016: Oncotarget
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"