Journal articles: 'Patched drug efflux inhibitors'

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Hasanovic, Anida, Méliné Simsir, Frank S. Choveau, Enzo Lalli, and Isabelle Mus-Veteau. "Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity." Biomedicines 8, no. 8 (July 29, 2020): 251. http://dx.doi.org/10.3390/biomedicines8080251.

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Adrenocortical carcinoma (ACC) presents a high risk of relapse and metastases with outcomes not improving despite extensive research and new targeted therapies. We recently showed that the Hedgehog receptor Patched is expressed in ACC, where it strongly contributes to doxorubicin efflux and treatment resistance. Here, we report the identification of a new inhibitor of Patched drug efflux, the anti-histaminergic drug astemizole. We show that astemizole enhances the cytotoxic, proapoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells at concentrations of astemizole or doxorubicin that are not effective by themselves. Our results suggest that a low concentration of astemizole sensitizes ACC cells to doxorubicin, which is a component of the standard treatment for ACC composed of etoposide, doxorubicin, cisplatin and mitotane (EDPM). Patched uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that the use of astemizole or a derivative in combination with EDPM could be a promising therapeutic option for ACC by increasing the treatment effectiveness at lower doses of EDPM, which would reduce the severe side effects of this regimen.

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Signetti, Laurie, Nelli Elizarov, Méliné Simsir, Agnès Paquet, Dominique Douguet, Fabien Labbal, Delphine Debayle, et al. "Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma." Cancers 12, no. 6 (June 9, 2020): 1500. http://dx.doi.org/10.3390/cancers12061500.

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Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAFV600E melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that PAH is a highly promising lead for the treatment of vemurafenib resistant BRAFV600E melanoma.

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Mdluli, Khisimuzi E., Pamela R. Witte, Toni Kline, Adam W. Barb, Alice L. Erwin, Bryce E. Mansfield, Amanda L. McClerren, et al. "Molecular Validation of LpxC as an Antibacterial Drug Target in Pseudomonas aeruginosa." Antimicrobial Agents and Chemotherapy 50, no. 6 (June 2006): 2178–84. http://dx.doi.org/10.1128/aac.00140-06.

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ABSTRACT LpxC [UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc deacetylase] is a metalloamidase that catalyzes the first committed step in the biosynthesis of the lipid A component of lipopolysaccharide. A previous study (H. R. Onishi, B. A. Pelak, L. S. Gerckens, L. L. Silver, F. M. Kahan, M. H. Chen, A. A. Patchett, S. M. Galloway, S. A. Hyland, M. S. Anderson, and C. R. H. Raetz, Science 274:980-982, 1996) identified a series of synthetic LpxC-inhibitory molecules that were bactericidal for Escherichia coli. These molecules did not inhibit the growth of Pseudomonas aeruginosa and were therefore not developed further as antibacterial drugs. The inactivity of the LpxC inhibitors for P. aeruginosa raised the possibility that LpxC activity might not be essential for all gram-negative bacteria. By placing the lpxC gene of P. aeruginosa under tight control of an arabinose-inducible promoter, we demonstrated the essentiality of LpxC activity for P. aeruginosa. It was found that compound L-161,240, the most potent inhibitor from the previous study, was active against a P. aeruginosa construct in which the endogenous lpxC gene was inactivated and in which LpxC activity was supplied by the lpxC gene from E. coli. Conversely, an E. coli construct in which growth was dependent on the P. aeruginosa lpxC gene was resistant to the compound. The differential activities of L-161,240 against the two bacterial species are thus the result primarily of greater potency toward the E. coli enzyme rather than of differences in the intrinsic resistance of the bacteria toward antibacterial compounds due to permeability or efflux. These data validate P. aeruginosa LpxC as a target for novel antibiotic drugs and should help direct the design of inhibitors against clinically important gram-negative bacteria.

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Kovachka, Sandra, Giuliano Malloci, Attilio Vittorio Vargiu, Stéphane Azoulay, Isabelle Mus-Veteau, and Paolo Ruggerone. "Molecular insights into the Patched1 drug efflux inhibitory activity of panicein A hydroquinone: a computational study." Physical Chemistry Chemical Physics 23, no. 13 (2021): 8013–22. http://dx.doi.org/10.1039/d0cp05719c.

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Lu, Rong, Yun Zhou, Jinqian Ma, Yuchen Wang, and Xiaoqing Miao. "Strategies and Mechanism in Reversing Intestinal Drug Efflux in Oral Drug Delivery." Pharmaceutics 14, no. 6 (May 26, 2022): 1131. http://dx.doi.org/10.3390/pharmaceutics14061131.

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Efflux transporters distributed at the apical side of human intestinal epithelial cells actively transport drugs from the enterocytes to the intestinal lumen, which could lead to extremely poor absorption of drugs by oral administration. Typical intestinal efflux transporters involved in oral drug absorption process mainly include P-glycoprotein (P-gp), multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP). Drug efflux is one of the most important factors resulting in poor absorption of oral drugs. Caco-2 monolayer and everted gut sac are sued to accurately measure drug efflux in vitro. To reverse intestinal drug efflux and improve absorption of oral drugs, a great deal of functional amphiphilic excipients and inhibitors with the function of suppressing efflux transporters activity are generalized in this review. In addition, different strategies of reducing intestinal drugs efflux such as silencing transporters and the application of excipients and inhibitors are introduced. Ultimately, various nano-formulations of improving oral drug absorption by inhibiting intestinal drug efflux are discussed. In conclusion, this review has significant reference for overcoming intestinal drug efflux and improving oral drug absorption.

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Sreekantan, Abhirami P., Pooja P. Rajan, Minsa Mini, and Praveen Kumar. "Multidrug Efflux Pumps in Bacteria and Efflux Pump Inhibitors." Postępy Mikrobiologii - Advancements of Microbiology 61, no. 3 (September 1, 2022): 105–14. http://dx.doi.org/10.2478/am-2022-009.

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Abstract Antimicrobial resistance is becoming a paramount health concern nowadays. The increasing drug resistance in microbes is due to improper medications or over usage of drugs. Bacteria develop many mechanisms to extrude the antibiotics entering the cell. The most prominent are the efflux pumps (EPs). EPs play a significant role in intrinsic and acquired bacterial resistance, mainly in Gram-negative bacteria. EPs may be unique to one substrate or transport several structurally different compounds (including multi-class antibiotics). These pumps are generally associated with multiple drug resistance (MDR). EPs are energized by a proton motive force and can pump a vast range of detergents, drugs, antibiotics and also β-lactams, which are impermeable to the cytoplasmic membrane. There are five leading efflux transporter families in the prokaryotic kingdom: MF (Major Facilitator), MATE (Multidrug And Toxic Efflux), RND (Resistance-Nodulation-Division), SMR (Small Multidrug Resistance) and ABC (ATP Binding Cassette). Apart from the ABC family, which utilizes ATP hydrolysis to drive the export of substrates, all other systems use the proton motive force as an energy source. Some molecules known as Efflux Pump Inhibitors (EPI) can inhibit EPs in Gram-positive and Gram-negative bacteria. EPIs can interfere with the efflux of antimicrobial agents, leading to an increase in the concentration of antibiotics inside the bacterium, thus killing it. Therefore, identifying new EPIs appears to be a promising strategy for countering antimicrobial drug resistance (AMR). This mini-review focuses on the major efflux transporters of the bacteria and the progress in identifying Efflux Pump Inhibitors.

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Pleban, Karin, Dominik Kaiser, Stefan Kopp, Michael Peer, Peter Chiba, and Gerhard F. Ecker. "Targeting drug-efflux pumps -- a pharmacoinformatic approach." Acta Biochimica Polonica 52, no. 3 (August 4, 2005): 737–40. http://dx.doi.org/10.18388/abp.2005_3439.

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In line with our studies on propafenone-type inhibitors of P-glycoprotein (P-gp), we applied several methods to approach virtual screening tools for identification of new P-gp inhibitors on one hand and the molecular basis of ligand-protein interaction on the other hand. For virtual screening, a combination of autocorrelation vectors and selforganising artificial neural networks proved extremely valuable in identifying P-gp inhibitors with structurally new scaffolds. For a closer view on the binding region for propafenone-type ligands we applied a combination of pharmacophore-driven photoaffinity labeling and protein homology modeling. On LmrA, a bacterial homologue of P-gp, we were able to identify distinct regions on transmembrane helices 3, 5 and 6 which show significant changes in the labeling pattern during different steps of the catalytic cycle.

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Zhang, Lan, Xiaoyuan Tian, Lei Sun, Kun Mi, Ru Wang, Fengying Gong, and Lingli Huang. "Bacterial Efflux Pump Inhibitors Reduce Antibiotic Resistance." Pharmaceutics 16, no. 2 (January 25, 2024): 170. http://dx.doi.org/10.3390/pharmaceutics16020170.

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Bacterial resistance is a growing problem worldwide, and the number of deaths due to drug resistance is increasing every year. We must pay great attention to bacterial resistance. Otherwise, we may go back to the pre-antibiotic era and have no drugs on which to rely. Bacterial resistance is the result of several causes, with efflux mechanisms widely recognised as a significant factor in the development of resistance to a variety of chemotherapeutic and antimicrobial medications. Efflux pump inhibitors, small molecules capable of restoring the effectiveness of existing antibiotics, are considered potential solutions to antibiotic resistance and have been an active area of research in recent years. This article provides a review of the efflux mechanisms of common clinical pathogenic bacteria and their efflux pump inhibitors and describes the effects of efflux pump inhibitors on biofilm formation, bacterial virulence, the formation of bacterial persister cells, the transfer of drug resistance among bacteria, and mismatch repair. Numerous efforts have been made in the past 20 years to find novel efflux pump inhibitors which are known to increase the effectiveness of medicines against multidrug-resistant strains. Therefore, the application of efflux pump inhibitors has excellent potential to address and reduce bacterial resistance.

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Balganesh, Meenakshi, Neela Dinesh, Sreevalli Sharma, Sanjana Kuruppath, Anju V. Nair, and Umender Sharma. "Efflux Pumps of Mycobacterium tuberculosis Play a Significant Role in Antituberculosis Activity of Potential Drug Candidates." Antimicrobial Agents and Chemotherapy 56, no. 5 (February 6, 2012): 2643–51. http://dx.doi.org/10.1128/aac.06003-11.

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ABSTRACTActive efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. To understand these efflux mechanisms inMycobacterium tuberculosis, we generated knockout (KO) mutants of four efflux pumps of the pathogen belonging to different classes. We measured the MICs and kill values of two different compound classes on the wild type (WT) and the efflux pump (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil andl-phenylalanyl-l-arginyl-β-naphthylamide (PAβN). Among the pumps studied, the efflux pumps belonging to the ABC (ATP-binding cassette) class, encoded byRv1218c, and the SMR (small multidrug resistance) class, encoded byRv3065, appear to play important roles in mediating the efflux of different chemical classes and antibiotics. Efflux pumps encoded byRv0849andRv1258calso mediate the efflux of these compounds, but to a lesser extent. Increased killing is observed in WTM. tuberculosiscells by these compounds in the presence of either verapamil or PAβN. The efflux pump KO mutants were more susceptible to these compounds in the presence of efflux inhibitors. We have shown that these four efflux pumps ofM. tuberculosisplay a vital role in mediating efflux of different chemical scaffolds. Inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis. The identification and characterization ofRv0849, a new efflux pump belonging to the MFS (major facilitator superfamily) class, are reported.

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Bernkop-Schn??rch, Andreas, and Vjera Grabovac. "Polymeric Efflux Pump Inhibitors in Oral Drug Delivery." American Journal of Drug Delivery 4, no. 4 (2006): 263–72. http://dx.doi.org/10.2165/00137696-200604040-00008.

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Rindi, Laura. "Efflux Pump Inhibitors against Nontuberculous Mycobacteria." International Journal of Molecular Sciences 21, no. 12 (June 12, 2020): 4191. http://dx.doi.org/10.3390/ijms21124191.

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Over the last years, nontuberculous mycobacteria (NTM) have emerged as important human pathogens. Infections caused by NTM are often difficult to treat due to an intrinsic multidrug resistance for the presence of a lipid-rich outer membrane, thus encouraging an urgent need for the development of new drugs for the treatment of mycobacterial infections. Efflux pumps (EPs) are important elements that are involved in drug resistance by preventing intracellular accumulation of antibiotics. A promising strategy to decrease drug resistance is the inhibition of EP activity by EP inhibitors (EPIs), compounds that are able to increase the intracellular concentration of antimicrobials. Recently, attention has been focused on identifying EPIs in mycobacteria that could be used in combination with drugs. The aim of the present review is to provide an overview of the current knowledge on EPs and EPIs in NTM and also, the effect of potential EPIs as well as their combined use with antimycobacterial drugs in various NTM species are described.

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Amr A, Baiomy, Shaker Ghada H, and Abbas Hisham A. "Sensitizing multi drug resistant Staphylococcus aureus isolated from surgical site infections to antimicrobials by efflux pump inhibitors." African Health Sciences 20, no. 4 (December 16, 2020): 1632–45. http://dx.doi.org/10.4314/ahs.v20i4.16.

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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.

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Rodrigues, Liliana, Jose A. Ainsa, Leonard Amaral, and Miguel Viveiros. "Inhibition of Drug Efflux in Mycobacteria with Phenothiazines and Other Putative Efflux Inhibitors." Recent Patents on Anti-Infective Drug Discovery 6, no. 2 (May 1, 2011): 118–27. http://dx.doi.org/10.2174/157489111796064579.

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Monteiro, Kadja Luana Chagas, Thiago Mendonça de Aquino, and Francisco Jaime B. Mendonça Junior. "An Update on Staphylococcus aureus NorA Efflux Pump Inhibitors." Current Topics in Medicinal Chemistry 20, no. 24 (November 2, 2020): 2168–85. http://dx.doi.org/10.2174/1568026620666200704135837.

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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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Zárate, Sandra, Paula Morales, Katarzyna Świderek, Victor Bolanos-Garcia, and Agatha Bastida. "A Molecular Modeling Approach to Identify Novel Inhibitors of the Major Facilitator Superfamily of Efflux Pump Transporters." Antibiotics 8, no. 1 (March 15, 2019): 25. http://dx.doi.org/10.3390/antibiotics8010025.

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Multidrug efflux systems play a prominent role in medicine, as they are important contributors to bacterial antibiotic resistance. NorA is an efflux pump transporter from the major facilitator superfamily that expels numerous drug compounds across the inner membrane of Staphylococcus aureus (S. aureus). The design of novel inhibitors to combat drug efflux could offer new opportunities to avoid the problem of antibiotic resistance. In this study, we performed molecular modeling studies in an effort to discover novel NorA efflux pump inhibitors. A group of over 673 compounds from the PubChem database with a high (>80%) level of similarity to the chemical structure of capsaicin was used to study the binding affinity of small molecule compounds for the NorA efflux pump. Ten potential lead compounds displayed a good druggability profile, with one in particular (CID 44330438) providing new insight into the molecular mechanism of the inhibition of major facilitator superfamily (MFS) efflux pump transporters. It is our hope that the overall strategy described in this study, and the structural information of the potential novel inhibitors thus identified, will stimulate others to pursue the development of better drugs to tackle multidrug resistance in S. aureus.

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Wang, Yinhu, Henrietta Venter, and Shutao Ma. "Efflux Pump Inhibitors: A Novel Approach to Combat Efflux-Mediated Drug Resistance in Bacteria." Current Drug Targets 17, no. 6 (March 24, 2016): 702–19. http://dx.doi.org/10.2174/1389450116666151001103948.

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Mullin, Steve, Nagraj Mani, and Trudy H. Grossman. "Inhibition of Antibiotic Efflux in Bacteria by the Novel Multidrug Resistance Inhibitors Biricodar (VX-710) and Timcodar (VX-853)." Antimicrobial Agents and Chemotherapy 48, no. 11 (November 2004): 4171–76. http://dx.doi.org/10.1128/aac.48.11.4171-4176.2004.

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ABSTRACT Inhibitors of mammalian multidrug efflux, such as the plant alkaloid reserpine, are also active in potentiating antibiotic activity by inhibiting bacterial efflux. Based on this precedent, two novel mammalian multiple drug resistance inhibitors, biricodar (VX-710) and timcodar (VX-853), were evaluated for activity in a variety of bacteria. Both VX-710 and VX-853 potentiated the activity of ethidium bromide (EtBr), a model efflux substrate, against three clinically significant gram-positive pathogens: Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae. Similar to reserpine, VX-710 and VX-853 directly blocked EtBr efflux in S. aureus. Furthermore, these compounds were effective in lowering the MICs of several clinically used antibiotics, including fluoroquinolones, suggesting that VX-710 and VX-853 are representatives of a new class of bacterial efflux inhibitors with the potential for use in combination therapy.

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Chevalier, Jacqueline, Jérôme Bredin, Abdallah Mahamoud, Monique Malléa, Jacques Barbe, and Jean-Marie Pagès. "Inhibitors of Antibiotic Efflux in Resistant Enterobacter aerogenes and Klebsiella pneumoniae Strains." Antimicrobial Agents and Chemotherapy 48, no. 3 (March 2004): 1043–46. http://dx.doi.org/10.1128/aac.48.3.1043-1046.2004.

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ABSTRACT In Enterobacter aerogenes and Klebsiella pneumoniae, efflux provides efficient extrusion of antibiotics and contributes to the multidrug resistance phenotype. One of the alkoxyquinoline derivatives studied here, 2,8-dimethyl-4-(2′-pyrrolidinoethyl)-oxyquinoline, restores noticeable drug susceptibility to resistant clinical strains. Analyses of energy-dependent chloramphenicol efflux indicate that this compound inhibits the efflux pump mechanism and improves the activity of structurally unrelated antibiotics on multidrug-resistant E. aerogenes and K. pneumoniae isolates.

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Ramón-García, Santiago, Carlos Martín, Charles J. Thompson, and José A. Aínsa. "Role of the Mycobacterium tuberculosis P55 Efflux Pump in Intrinsic Drug Resistance, Oxidative Stress Responses, and Growth." Antimicrobial Agents and Chemotherapy 53, no. 9 (June 29, 2009): 3675–82. http://dx.doi.org/10.1128/aac.00550-09.

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ABSTRACT Bacterial efflux pumps have traditionally been studied as low-level drug resistance determinants. Recent insights have suggested that efflux systems are often involved with fundamental cellular physiological processes, suggesting that drug extrusion may be a secondary function. In Mycobacterium tuberculosis, little is known about the physiological or drug resistance roles of efflux pumps. Using Mycobacterium bovis BCG as a model system, we showed that deletion of the Rv1410c gene encoding the P55 efflux pump made the strain more susceptible to a range of toxic compounds, including rifampin (rifampicin) and clofazimine, which are first- and second-line antituberculosis drugs. The efflux pump inhibitors carbonyl cyanide m-chlorophenylhydrazone (CCCP) and valinomycin inhibited the P55-determined drug resistance, suggesting the active export of the compounds by use of the transmembrane proton and electrochemical gradients as sources of energy. In addition, the P55 efflux pump mutant was more susceptible to redox compounds and displayed increased intracellular redox potential, suggesting an essential role of the efflux pump in detoxification processes coupled to oxidative balance within the cell. Finally, cells that lacked the p55 gene displayed smaller colony sizes and had a growth defect in liquid culture. This, together with an increased susceptibility to the cell wall-targeting compounds bacitracin and vancomycin, suggested that P55 is needed for proper cell wall assembly and normal growth in vitro. Thus, P55 plays a fundamental role in oxidative stress responses and in vitro cell growth, in addition to contributing to intrinsic antibiotic resistance. Inhibitors of the P55 efflux pump could help to improve current treatments for tuberculosis.

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Montanari, Floriane, Anna Cseke, Katrin Wlcek, and Gerhard F. Ecker. "Virtual Screening of DrugBank Reveals Two Drugs as New BCRP Inhibitors." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 1 (July 11, 2016): 86–93. http://dx.doi.org/10.1177/1087057116657513.

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The breast cancer resistance protein (BCRP) is an ABC transporter playing a crucial role in the pharmacokinetics of drugs. The early identification of substrates and inhibitors of this efflux transporter can help to prevent or foresee drug-drug interactions. In this work, we built a ligand-based in silico classification model to predict the inhibitory potential of drugs toward BCRP. The model was applied as a virtual screening technique to identify potential inhibitors among the small-molecules subset of DrugBank. Ten compounds were selected and tested for their capacity to inhibit mitoxantrone efflux in BCRP-expressing PLB985 cells. Results identified cisapride (IC50 = 0.4 µM) and roflumilast (IC50 = 0.9 µM) as two new BCRP inhibitors. The in silico strategy proved useful to prefilter potential drug-drug interaction perpetrators among a database of small molecules and can reduce the amount of compounds to test.

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Lee, May D., Jorge L. Galazzo, Andrew L. Staley, Julie C. Lee, Mark S. Warren, Hans Fuernkranz, Suzanne Chamberland, Olga Lomovskaya, and George H. Miller. "Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance." Il Farmaco 56, no. 1-2 (March 2001): 81–85. http://dx.doi.org/10.1016/s0014-827x(01)01002-3.

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Werle, Martin. "Natural and Synthetic Polymers as Inhibitors of Drug Efflux Pumps." Pharmaceutical Research 25, no. 3 (September 26, 2007): 500–511. http://dx.doi.org/10.1007/s11095-007-9347-8.

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Kourtesi, Christina, Anthony R. Ball, Ying-Ying Huang, Sanjay M. Jachak, D. Mariano A. Vera, Proma Khondkar, Simon Gibbons, Michael R. Hamblin, and George P. Tegos. "Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation." Open Microbiology Journal 7, no. 1 (March 22, 2013): 34–52. http://dx.doi.org/10.2174/1874285801307010034.

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Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches.

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Döring, Henry, David Kreutzer, Christoph Ritter, and Andreas Hilgeroth. "Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy." Molecules 26, no. 1 (December 22, 2020): 18. http://dx.doi.org/10.3390/molecules26010018.

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Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.

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Pulukuri, Anunay J., Anthony J. Burt, Larissa K. Opp, Colin M. McDowell, Maryam Davaritouchaee, Amy E. Nielsen, and Rock J. Mancini. "Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein." Pharmaceuticals 14, no. 12 (December 10, 2021): 1292. http://dx.doi.org/10.3390/ph14121292.

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Multidrug-Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux, a process that transports drugs from within a cell to the extracellular space via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR) agonist immunotherapies modulate activity of tumor-infiltrating immune cells in local proximity to cancer cells and could, therefore, benefit from the enhanced drug efflux in MDR cancers. However, the effect of acquired drug resistance on TLR agonist efflux is largely unknown. We begin to address this by investigating P-gp mediated efflux of TLR 7/8 agonists. First, we used functionalized liposomes to determine that imidazoquinoline TLR agonists Imiquimod, Resiquimod, and Gardiquimod are substrates for P-gp. Interestingly, the least potent imidazoquinoline (Imiquimod) was the best P-gp substrate. Next, we compared imidazoquinoline efflux in MDR cancer cell lines with enhanced P-gp expression relative to parent cancer cell lines. Using P-gp competitive substrates and inhibitors, we observed that imidazoquinoline efflux occurs through P-gp and, for Imiquimod, is enhanced as a consequence of acquired drug resistance. This suggests that enhancing efflux susceptibility could be an important consideration in the rational design of next generation immunotherapies that modulate activity of tumor-infiltrating immune cells.

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Lu, Wen-Jung, Pang-Hung Hsu, Chun-Ju Chang, Cheng-Kuan Su, Yan-Jyun Huang, Hsuan-Ju Lin, Margaret Lai, Gui-Xia Ooi, Jing-Yi Dai, and Hong-Ting Victor Lin. "Identified Seaweed Compound Diphenylmethane Serves as an Efflux Pump Inhibitor in Drug-Resistant Escherichia coli." Antibiotics 10, no. 11 (November 10, 2021): 1378. http://dx.doi.org/10.3390/antibiotics10111378.

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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.

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Brown, Adam R., Keivan A. Ettefagh, Daniel A. Todd, Patrick S. Cole, Joseph M. Egan, Daniel H. Foil, Elizabeth P. Lacey, and Nadja B. Cech. "Bacterial efflux inhibitors are widely distributed in land plants." Journal of Ethnopharmacology 267 (March 2021): 113533. http://dx.doi.org/10.1016/j.jep.2020.113533.

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Avci, Fatma Gizem, Basak Atas, Cemile Selin Aksoy, Eldin Kurpejovic, Gizem Gulsoy Toplan, Caglayan Gurer, Maxime Guillerminet, Cedric Orelle, Jean-Michel Jault, and Berna Sariyar Akbulut. "Repurposing bioactive aporphine alkaloids as efflux pump inhibitors." Fitoterapia 139 (November 2019): 104371. http://dx.doi.org/10.1016/j.fitote.2019.104371.

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Jamshidi, Shirin, J. Mark Sutton, and Khondaker M. Rahman. "An overview of bacterial efflux pumps and computational approaches to study efflux pump inhibitors." Future Medicinal Chemistry 8, no. 2 (February 2016): 195–210. http://dx.doi.org/10.4155/fmc.15.173.

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Kharangarh, Sahil, Hardeep Sandhu, Sujit Tangadpalliwar, and Prabha Garg. "Predicting Inhibitors for Multidrug Resistance Associated Protein-2 Transporter by Machine Learning Approach." Combinatorial Chemistry & High Throughput Screening 21, no. 8 (December 17, 2018): 557–66. http://dx.doi.org/10.2174/1386207321666181024104822.

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Background: The efflux transporter multidrug resistance associated protein-2 belongs to ATP-binding cassette superfamily which plays an important role in multidrug resistance and drugdrug interactions. Efflux transporters are considered to be important targets for increasing the efficacy of drugs and importance of computational study of efflux transporters for predicting substrates, non-substrates, inhibitors and non-inhibitors is well documented. Previous work on predictive models for inhibitors of multidrug resistance associated Protein-2 efflux transporter showed that machine learning methods produced good results. Objective: The aim of the present work was to develop a machine learning predictive model to classify inhibitors and non-inhibitors of multidrug resistance associated protein-2 transporter using a well refined dataset. Method: In this study, the various algorithms of machine learning were used to develop the predictive models i.e. support vector machine, random forest and k-nearest neighbor. The methods like variance threshold, SelectKBest, random forest, and recursive feature elimination were used to select the features generated by PyDPI. A total of 239 molecules consisting of 124 inhibitors and 115 non-inhibitors were used for model development. Results: The best multidrug resistance associated protein-2 inhibitor model showed prediction accuracies of 0.76, 0.72 and 0.79 for training, 5-fold cross-validation and external sets, respectively. Conclusion: It was observed that support vector machine model built on features selected using recursive feature elimination method shows the best performance. The developed model can be used in the early stages of drug discovery for identifying the inhibitors of multidrug resistance associated protein-2 efflux transporter.

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Zack, Kira M., Trent Sorenson, and Suresh G. Joshi. "Types and Mechanisms of Efflux Pump Systems and the Potential of Efflux Pump Inhibitors in the Restoration of Antimicrobial Susceptibility, with a Special Reference to Acinetobacter baumannii." Pathogens 13, no. 3 (February 23, 2024): 197. http://dx.doi.org/10.3390/pathogens13030197.

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Bacteria express a plethora of efflux pumps that can transport structurally varied molecules, including antimicrobial agents and antibiotics, out of cells. Thus, efflux pump systems participate in lowering intracellular concentrations of antibiotics, which allows phenotypic multidrug-resistant (MDR) bacteria to survive effectively amid higher concentrations of antibiotics. Acinetobacter baumannii is one of the classic examples of pathogens that can carry multiple efflux pump systems, which allows these bacteria to be MDR-to-pan-drug resistant and is now considered a public health threat. Therefore, efflux pumps in A. baumannii have gained major attention worldwide, and there has been increased interest in studying their mechanism of action, substrates, and potential efflux pump inhibitors (EPIs). Efflux pump inhibitors are molecules that can inhibit efflux pumps, rendering pathogens susceptible to antimicrobial agents, and are thus considered potential therapeutic agents for use in conjunction with antibiotics. This review focuses on the types of various efflux pumps detected in A. baumannii, their molecular mechanisms of action, the substrates they transport, and the challenges in developing EPIs that can be clinically useful in reference to A. baumannii.

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Sibandze, G., P. Stapleton, and S. Gibbons. "Efflux inhibitors from Swazi medicinal plants." Planta Medica 81, S 01 (December 14, 2016): S1—S381. http://dx.doi.org/10.1055/s-0036-1596404.

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Phan, Thien-Vy, Cao-Hoang-Hao Nguyen, and Vu-Thuy-Vy Nguyen. "3D-Pharmacophore and Molecular Docking Studies for AcrAB-TolC Efflux Pump Potential Inhibitors from DrugBank and Traditional Chinese Medical Database." Open Access Macedonian Journal of Medical Sciences 10, A (November 25, 2022): 1659–67. http://dx.doi.org/10.3889/oamjms.2022.11081.

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Background: Due to the widespread resistance to several antibiotics, the AcrAB-TolC tripartite efflux pump is the primary multi-drug efflux system of Escherichia coli. One of the most promising treatments since the discovery of efflux pump inhibitors is the combination of them with antibiotics. AIM: Based on the efflux pump inhibitor database and the structure of AcrB, the research was created the virtual screening models with prediction capabilities for the efflux pump inhibitory effects of candidates from the DrugBank and Traditional Chinese Medical databank. Methods: The pharmacophore models were developed by MOE 2015.10 software using a database of 119 efflux pump inhibitors discovered in 12 research publications and belonged to different structural classes. The binding site was found on the AcrB protein (PDB: 4DX7) by LeadIT 2.0.2 software that corresponds to the hydrophobic trap in the proximal pocket. Results: The potential inhibitors which satisfied the pharmacophore model and had docking scores under -20 kJ.mol-1 have been established. In which, TCM_20290, DB00303, DB04642, DB08116, TCM_29530, and 2,5-dimethyl-3-O-D-glucopyranosyl-naphthol have the best docking scores of -32.76, -26.59, -26.14, -25.62, -24.88, and -22.82 kJ.mol-1, respectively. Conclusions: After the screening, the result was obtained six compounds may be potential efflux pump inhibitors that can be used for additional studies. In the future, further in vitro and in vivo research should be required to confirm the effects of these compounds. The ongoing battle against antibiotic resistance shows promise with the finding on initiators that can obstruct AcrAB–TolC multidrug efflux pumps. Keywords: AcrAB-TolC, inhibitors, Escherichia coli, pharmacophore, molecular docking.

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Durães, Fernando, Madalena Pinto, and Emília Sousa. "Medicinal Chemistry Updates on Bacterial Efflux Pump Modulators." Current Medicinal Chemistry 25, no. 42 (February 6, 2019): 6030–69. http://dx.doi.org/10.2174/0929867325666180209142612.

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Antibiotic resistance is one of the most pressing health issues of our days. It can arise due to a multiplicity of factors, such as target modification, decrease in the drug uptake, changes in the metabolic pathways and activation of efflux pumps. The overexpression of efflux pumps is responsible for the extrusion of drugs, making antibiotic therapy fail, as the quantity of intracellular antibiotic is not enough to provide the desired therapeutic effect. Efflux pumps can be included in five families according to their composition, nature of substrates, energy source, and number of transmembrane spanning regions. The ABC superfamily is mainly found in Gram-positive bacteria, use ATP as an energy source, and only a limited number of ABC pumps confer multidrug resistance (MDR). On the other hand, the MFS family, most present in Gram-positive bacteria, and the RND family, characteristic of Gram-negative bacteria, are most associated with antibiotic resistance. A wide variety of inhibitors have been disclosed for both families, from either natural or synthetic sources, or even drugs that are currently in therapy for other diseases. The other two families are the SMR, which are the smallest drug efflux proteins known, and the MATE family, whose pumps can also resort to the sodium gradient as an energy source. In this review, it is intended to present a comprehensive review of the classes of efflux pump inhibitors from the various sources, highlighting their structure-activity relationships, which can be useful for medicinal chemists in the pursuit of novel efflux pump inhibitors.

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Kamaz, Zahraa Ali, Haruna Isiyaku Umar, Parth Doshi, and Praveenya Suri. "Glycosylated Antibiotics: New Promising Bacterial Efflux Pumps Inhibitors." Microbiology Research Journal International 34, no. 3 (April 5, 2024): 48–59. http://dx.doi.org/10.9734/mrji/2024/v34i31435.

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Antimicrobial resistance is considered a major concern problem; bacteria have evolved mechanisms to overcome antibiotics’ action through evolutionary process. One main resistance mechanism that bacteria developed is the pumping of the antibiotics out of bacterial cells by transmembrane transporter proteins known as efflux pumps. To overcome bacterial resistance guided by efflux pumps, efflux pumps inhibitors (EPIs) are small molecules that obstruct efflux pumps binding sites and its structural assembly leading to disability in the efflux pumps normal function, new EPIs which under the current study are created by modifying the chemical structure of most common antibiotics including Ampicillin, Penicillin, Chloramphenicol, Ciprofloxacin and Tetracycline, such antibiotics are modified by adding N-acetyl glucose amine moiety to acceptor OH group of the respective antibiotic, the newly modified antibiotics are glycosylated EPIs. To test the effectiveness of the new EPIs in inhibiting AcrB-TolC and MexA-OprM efflux pumps functions, ADME properties for all of glycosylated antibiotics have been measured through applying Lipinski’s role of 5, docking and simulation studies have been included as well. Docked glycosylated tetracycline has given the highest binding energy in the active sites of both pumps, with -9.4 against AcrB and -8.8 against MexA. The simulation study has confirmed the binding of the glycosylated tetracycline in the active sites of both pumps, as well as its stability during the biological dynamicity of both pumps (opening and closing channels). The results validation requires a long simulation time about 50 ns or more which was un applicable due to cost limitation, however, the newly glycosylated antibiotics have promising results that might make it eligible as drug candidates to overcome bacterial resistance.

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Lu, Wen-Jung, Hsuan-Ju Lin, Pang-Hung Hsu, Margaret Lai, Jen-Yu Chiu, and Hong-Ting Victor Lin. "Brown and Red Seaweeds Serve as Potential Efflux Pump Inhibitors for Drug-Resistant Escherichia coli." Evidence-Based Complementary and Alternative Medicine 2019 (January 1, 2019): 1–12. http://dx.doi.org/10.1155/2019/1836982.

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Multidrug-resistant pathogens are a significant clinical problem. Efflux pump inhibitors (EPIs) can restore the activities of existing antibiotics by interfering with drug efflux pumps located in bacterial cell membranes. Seaweeds are important sources of biologically active metabolites of natural origin; however, their potential as EPIs remains uninvestigated. Here, functional extracts from the brown seaweeds Laminaria japonica and Sargassum horneri and the red seaweeds Gracilaria sp. and Porphyra dentata were evaluated as potential EPIs against drug-resistant Escherichia coli. All these extracts were found to potentiate the activities of drugs in modulation tests, although not to the same extent. Synergistic effects of the extracts and the drug clarithromycin were observed from the onset of Time-kill assays, with no evidence of bacterial regrowth. Ethidium bromide accumulation studies revealed that the efflux decreased in the presence of each extract, as indicated by the presence of EPIs. Most identified EPIs that have been discovered to date have aromatic structures, and the seaweed extracts were found to contain various terpenes, terpenoids, phenolic compounds, indoles, pyrrole derivatives, alkaloids, and halogenated aromatic compounds. Our study highlights the potential of these compounds of the seaweeds as drug EPIs.

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Diwischek, Florian, Joachim Morschhäuser, and Ulrike Holzgrabe. "Cerulenin Analogues as Inhibitors of Efflux Pumps in Drug-resistantCandida albicans." Archiv der Pharmazie 342, no. 3 (March 2009): 150–64. http://dx.doi.org/10.1002/ardp.200800160.

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Machado, Diana, Laura Fernandes, Sofia S. Costa, Rolando Cannalire, Giuseppe Manfroni, Oriana Tabarrini, Isabel Couto, Stefano Sabatini, and Miguel Viveiros. "Mode of action of the 2-phenylquinoline efflux inhibitor PQQ4R againstEscherichia coli." PeerJ 5 (April 26, 2017): e3168. http://dx.doi.org/10.7717/peerj.3168.

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Efflux pump inhibitors are of great interest since their use as adjuvants of bacterial chemotherapy can increase the intracellular concentrations of the antibiotics and assist in the battle against the rising of antibiotic-resistant bacteria. In this work, we have described the mode of action of the 2-phenylquinoline efflux inhibitor (4-(2-(piperazin-1-yl)ethoxy)-2-(4-propoxyphenyl) quinolone – PQQ4R), againstEscherichia coli,by studding its efflux inhibitory ability, its synergistic activity in combination with antibiotics, and compared its effects with the inhibitors phenyl-arginine-β-naphthylamide (PAβN) and chlorpromazine (CPZ). The results showed that PQQ4R acts synergistically, in a concentration dependent manner, with antibiotics known to be subject to efflux inE. colireducing their MIC in correlation with the inhibition of their efflux. Real-time fluorometry assays demonstrated that PQQ4R at sub-inhibitory concentrations promote the intracellular accumulation of ethidium bromide inhibiting its efflux similarly to PAβN or CPZ, well-known and described efflux pump inhibitors for Gram-negative bacteria and whose clinical usage is limited by their levels of toxicity at clinical and bacteriological effective concentrations. The time-kill studies showed that PQQ4R, at bactericidal concentrations, has a rapid antimicrobial activity associated with a fast decrease of the intracellular ATP levels. The results also indicated that the mode of action of PQQ4R involves the destabilization of theE. coliinner membrane potential and ATP production impairment, ultimately leading to efflux pump inhibition by interference with the energy required by the efflux systems. At bactericidal concentrations, membrane permeabilization increases and finally ATP is totally depleted leading to cell death. Since drug resistance mediated by the activity of efflux pumps depends largely on the proton motive force (PMF), dissipaters of PMF such as PQQ4R, can be regarded as future adjuvants of conventional therapy againstE. coliand other Gram-negative bacteria, especially their multidrug resistant forms. Their major limitation is the high toxicity for human cells at the concentrations needed to be effective against bacteria. Their future molecular optimization to improve the efflux inhibitory properties and reduce relative toxicity will optimize their potential for clinical usage against multi-drug resistant bacterial infections due to efflux.

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Marć, Małgorzata Anna, Annamária Kincses, Bálint Rácz, Muhammad Jawad Nasim, Muhammad Sarfraz, Carlos Lázaro-Milla, Enrique Domínguez-Álvarez, Claus Jacob, Gabriella Spengler, and Pedro Almendros. "Antimicrobial, Anticancer and Multidrug-Resistant Reversing Activity of Novel Oxygen-, Sulfur- and Selenoflavones and Bioisosteric Analogues." Pharmaceuticals 13, no. 12 (December 11, 2020): 453. http://dx.doi.org/10.3390/ph13120453.

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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.

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Rathi, Ekta, Avinash Kumar, and Suvarna G. Kini. "Computational approaches in efflux pump inhibitors: current status and prospects." Drug Discovery Today 25, no. 10 (October 2020): 1883–90. http://dx.doi.org/10.1016/j.drudis.2020.07.011.

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Durães, Fernando, Andreia Palmeira, Bárbara Cruz, Joana Freitas-Silva, Nikoletta Szemerédi, Luís Gales, Paulo Martins da Costa, et al. "Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors." Pharmaceuticals 14, no. 6 (June 15, 2021): 572. http://dx.doi.org/10.3390/ph14060572.

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The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) and the NorA, from the major facilitator superfamily. In bacteria, these structures can also favor virulence and adaptation mechanisms, such as quorum-sensing and the formation of biofilm. In this study, the design and synthesis of a library of thioxanthones as potential efflux pump inhibitors are described. The thioxanthone derivatives were investigated for their antibacterial activity and inhibition of efflux pumps, biofilm formation, and quorum-sensing. The compounds were also studied for their potential to interact with P-glycoprotein (P-gp, ABCB1), an efflux pump present in mammalian cells, and for their cytotoxicity in both mouse fibroblasts and human Caco-2 cells. The results concerning the real-time ethidium bromide accumulation may suggest a potential bacterial efflux pump inhibition, which has not yet been reported for thioxanthones. Moreover, in vitro studies in human cells demonstrated a lack of cytotoxicity for concentrations up to 20 µM in Caco-2 cells, with some derivatives also showing potential for P-gp modulation.

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Lamut, Andraž, Lucija Peterlin Mašič, Danijel Kikelj, and Tihomir Tomašič. "Efflux pump inhibitors of clinically relevant multidrug resistant bacteria." Medicinal Research Reviews 39, no. 6 (April 19, 2019): 2460–504. http://dx.doi.org/10.1002/med.21591.

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Kochanek, Stanton J., David A. Close, Allen Xinwei Wang, Tongying Shun, Philip E. Empey, Julie L. Eiseman, and Paul A. Johnston. "Confirmation of Selected Synergistic Cancer Drug Combinations Identified in an HTS Campaign and Exploration of Drug Efflux Transporter Contributions to the Mode of Synergy." SLAS DISCOVERY: Advancing the Science of Drug Discovery 24, no. 6 (April 30, 2019): 653–68. http://dx.doi.org/10.1177/2472555219844566.

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Systematic unbiased high-throughput screening (HTS) of drug combinations (DCs) in well-characterized tumor cell lines is a data-driven strategy to identify novel DCs with potential to be developed into effective therapies. Four DCs from a DC HTS campaign were selected for confirmation; only one appears in clinicaltrials.gov and limited preclinical in vitro data indicates that the drug pairs interact synergistically. Nineteen DC-tumor cell line sets were confirmed to interact synergistically in three pharmacological interaction models. We developed an imaging assay to quantify accumulation of the ABCG2 efflux transporter substrate Hoechst. Gefitinib and raloxifene enhanced Hoechst accumulation in ABCG2 (BCRP)-expressing cells, consistent with inhibition of ABCG2 efflux. Both drugs also inhibit ABCB1 efflux. Mitoxantrone, daunorubicin, and vinorelbine are substrates of one or more of the ABCG2, ABCB1, or ABCC1 efflux transporters expressed to varying extents in the selected cell lines. Interactions between ABC drug efflux transporter inhibitors and substrates may have contributed to the observed synergy; however, other mechanisms may be involved. Novel synergistic DCs identified by HTS were confirmed in vitro, and plausible mechanisms of action studied. Similar approaches may justify the testing of novel HTS-derived DCs in mouse xenograft human cancer models and support the clinical evaluation of effective in vivo DCs in patients.

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Blanco, Paula, Fernando Sanz-García, Sara Hernando-Amado, José Luis Martínez, and Manuel Alcalde-Rico. "The development of efflux pump inhibitors to treat Gram-negative infections." Expert Opinion on Drug Discovery 13, no. 10 (September 10, 2018): 919–31. http://dx.doi.org/10.1080/17460441.2018.1514386.

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Zechini, Barbara, and Ilaria Versace. "Inhibitors of Multidrug Resistant Efflux Systems in Bacteria." Recent Patents on Anti-Infective Drug Discovery 4, no. 1 (January 1, 2009): 37–50. http://dx.doi.org/10.2174/157489109787236256.

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Alenazy, Rawaf. "Drug Efflux Pump Inhibitors: A Promising Approach to Counter Multidrug Resistance in Gram-Negative Pathogens by Targeting AcrB Protein from AcrAB-TolC Multidrug Efflux Pump from Escherichia coli." Biology 11, no. 9 (September 8, 2022): 1328. http://dx.doi.org/10.3390/biology11091328.

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Infections caused by multidrug resistance (MDR) of Gram-negative bacteria have become one of the most severe public health problems worldwide. The main mechanism that confers MDR to bacteria is drug efflux pumps, as they expel a wide range of compounds, especially antibiotics. Among the different types of drug efflux pumps, the resistance nodulation division (RND) superfamily confers MDR to various Gram-negative bacteria species. The AcrAB-TolC multidrug efflux pump, from E. coli, a member of RND, is the best-characterized example and an excellent model for understanding MDR because of an abundance of functional and structural data. Small molecule inhibitors that target the AcrAB-TolC drug efflux pump represent a new solution to reversing MDR in Gram-negative bacteria and restoring the efficacy of various used drugs that are clinically relevant to these pathogens, especially in the high shortage of drugs for multidrug-resistant Gram-negative bacteria. This review will investigate solutions of MDR in Gram-negative bacteria by studying the inhibition of the AcrAB-TolC multidrug efflux pump.

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AlMatar, Manaf, Işıl Var, Begüm Kayar, and Fatih Köksal. "Differential Expression of Resistant and Efflux Pump Genes in MDR-TB Isolates." Endocrine, Metabolic & Immune Disorders - Drug Targets 20, no. 2 (February 14, 2020): 271–87. http://dx.doi.org/10.2174/1871530319666191009153834.

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Background: Numerous investigations demonstrate efflux as a worldwide bacterial mode of action which contributes to the resistance of drugs. The activity of antibiotics, which subjects to efflux, can be improved by the combined usage of efflux inhibitors. However, the efflux role to the overall levels of antibiotic resistance of clinical M. tuberculosis isolates is inadequately comprehended and is still disregarded by many. Method: Here, we assessed the contribution of resistant genes associated with isoniazid (INH) and rifampin (R) resistance to the levels of drug resistance in the (27) clinical isolates of MDR-TB. Additionally, the role of the resistance for six putative drug efflux pump genes to the antibiotics was investigated. The level of katG expression was down-regulated in 24/27 (88.88%) of MDR-TB isolates. Of the 27 MDR-TB isolates, inhA, oxyR-ahpC, and rpoB showed either overexpression or up-regulation in 8 (29.62%), 4 (14.81 %), and 24 (88.88%), respectively. Moreover, the efflux pump genes drrA, drrB, efpA, Rv2459, Rv1634, and Rv1250 were overexpressed under INH/RIF plus fresh pomegranate juice (FPJ) stress signifying the efflux pumps contribution to the overall levels of the resistance of MDR-TB isolates. Conclusion: These results displayed that the levels of drug resistance of MDR-TB clinical isolates are due to combination among drug efflux pump and the presence of mutations in target genes, a truth which is often ignored by the specialists of tuberculosis in favour of the almost undoubted significance of drug target- gene mutations for the resistance in M. tuberculosis.

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Zwama, Martijn, and Kunihiko Nishino. "Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time." Antibiotics 10, no. 7 (June 25, 2021): 774. http://dx.doi.org/10.3390/antibiotics10070774.

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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.

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Nguyen, Thi Huyen Thu, Hai Dang Nguyen, Mai Huong Le, Thi Thu Hien Nguyen, Thi Dua Nguyen, Duc Long Nguyen, Quang Huy Nguyen, et al. "Efflux Pump Inhibitors in Controlling Antibiotic Resistance: Outlook under a Heavy Metal Contamination Context." Molecules 28, no. 7 (March 24, 2023): 2912. http://dx.doi.org/10.3390/molecules28072912.

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Multi-drug resistance to antibiotics represents a growing challenge in treating infectious diseases. Outside the hospital, bacteria with the multi-drug resistance (MDR) phenotype have an increased prevalence in anthropized environments, thus implying that chemical stresses, such as metals, hydrocarbons, organic compounds, etc., are the source of such resistance. There is a developing hypothesis regarding the role of metal contamination in terrestrial and aquatic environments as a selective agent in the proliferation of antibiotic resistance caused by the co-selection of antibiotic and metal resistance genes carried by transmissible plasmids and/or associated with transposons. Efflux pumps are also known to be involved in either antibiotic or metal resistance. In order to deal with these situations, microorganisms use an effective strategy that includes a range of expressions based on biochemical and genetic mechanisms. The data from numerous studies suggest that heavy metal contamination could affect the dissemination of antibiotic-resistant genes. Environmental pollution caused by anthropogenic activities could lead to mutagenesis based on the synergy between antibiotic efficacy and the acquired resistance mechanism under stressors. Moreover, the acquired resistance includes plasmid-encoded specific efflux pumps. Soil microbiomes have been reported as reservoirs of resistance genes that are available for exchange with pathogenic bacteria. Importantly, metal-contaminated soil is a selective agent that proliferates antibiotic resistance through efflux pumps. Thus, the use of multi-drug efflux pump inhibitors (EPIs) originating from natural plants or synthetic compounds is a promising approach for restoring the efficacy of existing antibiotics, even though they face a lot of challenges.

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Willers, Clarissa, Johannes Frederik Wentzel, Lissinda Hester du Plessis, Chrisna Gouws, and Josias Hendrik Hamman. "Efflux as a mechanism of antimicrobial drug resistance in clinical relevant microorganisms: the role of efflux inhibitors." Expert Opinion on Therapeutic Targets 21, no. 1 (December 5, 2016): 23–36. http://dx.doi.org/10.1080/14728222.2017.1265105.

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Journal articles on the topic 'Patched drug efflux inhibitors'

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