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Efflux pumps

Mitali Mishra, Satish Kumar, Rakesh K Majhi, Luna Goswami, Chandan Goswami, Harapriya Mohapatra
Antibacterial therapy is of paramount importance in treatment of several acute and chronic infectious diseases caused by pathogens. Over the years extensive use and misuse of antimicrobial agents has led to emergence of multidrug resistant (MDR) and extensive drug resistant (XDR) pathogens. This drastic escalation in resistant phenotype has limited the efficacy of available therapeutic options. Thus, the need of the hour is to look for alternative therapeutic approaches to mitigate healthcare concerns caused due to MDR bacterial infections...
2018: Frontiers in Microbiology
Martina Durcik, Denise Lovison, Žiga Skok, Cristina Durante Cruz, Päivi Tammela, Tihomir Tomašič, Davide Benedetto Tiz, Gábor Draskovits, Ákos Nyerges, Csaba Pál, Janez Ilaš, Lucija Peterlin Mašič, Danijel Kikelj, Nace Zidar
The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC50 values against DNA gyrase, and submicromolar IC50 values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E...
May 10, 2018: European Journal of Medicinal Chemistry
Jia-Feng Huang, Chun-Jie Wen, Guo-Zhi Zhao, Yi Dai, Ying Li, Lan-Xiang Wu, Hong-Hao Zhou
PURPOSE: Doxorubicin is one of the most active agents in the first-line therapy for metastatic breast cancer, but its utility is partially limited by the frequent emergence of doxorubicin resistance. In this study, we aimed to investigate the role of ATP-binding cassette sub-family B, member 4 (ABCB4) in acquired doxorubicin resistance in breast cancer cells, as well as its potential mechanism. METHODS: In doxorubicin-sensitive and -resistant breast cancer cell lines MCF-7 and MDA-MB-231, the expression levels of ABCB4 were detected using real-time quantitative PCR and Western blot analysis, the DNA methylation and histone acetylation status of ABCB4 gene were investigated by bisulfite-sequencing PCR (BSP) and chromatin immunoprecipitation (ChIP) assays, and the doxorubicin sensitivity and intracellular doxorubicin accumulation were observed using cell cytotoxicity assay and flow cytometry...
May 18, 2018: Cancer Chemotherapy and Pharmacology
Cláudia P Godinho, Catarina S Prata, Sandra N Pinto, Carlos Cardoso, Narcisa M Bandarra, Fábio Fernandes, Isabel Sá-Correia
Saccharomyces cerevisiae has the ability to become less sensitive to a broad range of chemically and functionally unrelated cytotoxic compounds. Among multistress resistance mechanisms is the one mediated by plasma membrane efflux pump proteins belonging to the ABC superfamily, questionably proposed to enhance the kinetics of extrusion of all these compounds. This study provides new insights into the biological role and impact in yeast response to acetic acid stress of the multistress resistance determinant Pdr18 proposed to mediate ergosterol incorporation in plasma membrane...
May 18, 2018: Scientific Reports
Yuki Yamasaki, Kaoru Kobayashi, Fuka Okuya, Naoyo Kajitani, Kanako Kazuki, Satoshi Abe, Shoko Takehara, Shingo Ito, Seiryo Ogata, Tatsuki Uemura, Sumio Ohtsuki, Genki Minegishi, Hidetaka Akita, Kan Chiba, Mitsuo Oshimura, Yasuhiro Kazuki
P-glycoprotein (P-gp), encoded by the MDR1 gene in humans and by the Mdr1a/1b genes in rodents, is expressed in numerous tissues and plays as an efflux pump to limit the distribution and absorption of many drugs. Owing to species differences of P-gp between humans and rodents, it is difficult to predict the impact of P-gp on pharmacokinetics and tissue distribution of P-gp substrates in humans from results of animal experiments. Therefore, we generated a novel P-gp humanized mouse model by using a mouse artificial chromosome (MAC) vector [designated human MDR1-MAC (hMDR1-MAC) mice]...
May 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Julia Vergalli, Estelle Dumont, Jelena Pajović, Bertrand Cinquin, Laure Maigre, Muriel Masi, Matthieu Réfrégiers, Jean-Marie Pagés
The efficacy of antibacterial molecules depends on their capacity to reach inhibitory concentrations in the vicinity of their target. This is particularly challenging for drugs directed against Gram-negative bacteria, which have a complex envelope comprising two membranes and efflux pumps. Precise determination of the bacterial drug content is an essential prerequisite for drug development. Here we describe three approaches that have been developed in our laboratories to quantify drugs accumulated in intact cells by spectrofluorimetry, microspectrofluorimetry, and kinetics microspectrofluorimetry (KMSF)...
June 2018: Nature Protocols
ShengLei Li, Ming Gao, ZongMing Li, LiJie Song, XianZheng Gao, Jing Han, Feng Wang, YongFang Chen, WenCai Li, JianPing Yang
Chemoresistance is a critical obstacle to the treatment of hepatocellular carcinoma (HCC). The mechanisms underlying resistance to doxorubicin, cisplatin, and 5-fluorouracil involve p53 and P-glycoprotein (P-gp). p53 plays a role in cell growth; therefore, resistance mechanisms involve chemotherapy-induced apoptosis and p53 mutation and inactivation. P-gp is an energy-dependent drug efflux pump regulated by p53. Its role in drug resistance has provided new insights into the mechanisms underlying the involvement of p53 and P-gp in chemoresistance and may alter our traditional understanding of p53 and P-gp function...
June 1, 2018: Frontiers in Bioscience (Elite Edition)
J C Cho, L M Childs-Kean, M T Zmarlicka, M P Crotty
Omadacycline is a novel aminomethylcycline antimicrobial agent that is available in both oral and intravenous formulations. The distinguishing structural characteristics of omadacycline from other tetracyclines allow for its continued antimicrobial activity in the presence of traditional tetracycline resistance mechanisms (efflux pumps and ribosomal protection proteins). Omadacycline has been found to have potent activity against antibiotic-resistant pathogens including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, extended spectrum beta-lactamase-producing Escherichia coli and multidrug-resistant Streptococcus pneumoniae...
March 2018: Drugs of Today
Shira Engelberg, Julia Modrejewski, Johanna G Walter, Yoav D Livney, Yehuda G Assaraf
Lung cancer is the leading cause of cancer mortality worldwide, resulting in 88% deaths of all diagnosed patients. Hence, novel therapeutic modalities are urgently needed. Single-stranded oligonucleotide-based aptamers (APTs) are excellent ligands for tumor cell targeting. However, the molecular mechanisms underlying their internalization into living cells have been poorly studied. Towards the application of APTs for active drug targeting to cancer cells, we herein studied the mechanism underlying S15-APT internalization into human non-small cell lung cancer A549 cells...
April 20, 2018: Oncotarget
De-Song Ming, Qing-Qing Chen, Xiao-Tin Chen
To clarify the resistance mechanisms of Pannonibacter phragmitetus 31801, isolated from the blood of a liver abscess patient, at the genomic level, we performed whole genomic sequencing using a PacBio RS II single-molecule real-time long-read sequencer. Bioinformatic analysis of the resulting sequence was then carried out to identify any possible resistance genes. Analyses included Basic Local Alignment Search Tool searches against the Antibiotic Resistance Genes Database, ResFinder analysis of the genome sequence, and Resistance Gene Identifier analysis within the Comprehensive Antibiotic Resistance Database...
May 14, 2018: Archives of Microbiology
Georg Basler, Mitchell Thompson, Danielle Tullman-Ercek, Jay Keasling
Background: The microbial production of biofuels is complicated by a tradeoff between yield and toxicity of many fuels. Efflux pumps enable bacteria to tolerate toxic substances by their removal from the cells while bypassing the periplasm. Their use for the microbial production of biofuels can help to improve cell survival, product recovery, and productivity. However, no native efflux pump is known to act on the class of short-chain alcohols, important next-generation biofuels, and it was considered unlikely that such an efflux pump exists...
2018: Biotechnology for Biofuels
Dianne J Watters
Ascidians (tunicates) are invertebrate chordates, and prolific producers of a wide variety of biologically active secondary metabolites from cyclic peptides to aromatic alkaloids. Several of these compounds have properties which make them candidates for potential new drugs to treat diseases such as cancer. Many of these natural products are not produced by the ascidians themselves, rather by their associated symbionts. This review will focus mainly on the mechanism of action of important classes of cytotoxic molecules isolated from ascidians...
May 13, 2018: Marine Drugs
Daniel A Charlebois, Junchen Diao, Dmitry Nevozhay, Gábor Balázsi
Synthetic biologists aim to design biological systems for a variety of industrial and medical applications, ranging from biofuel to drug production. Synthetic gene circuits regulating efflux pump protein expression can achieve this by driving desired substrates such as biofuels, pharmaceuticals, or other chemicals out of the cell in a precisely controlled manner. However, efflux pumps may introduce implicit negative feedback by pumping out intracellular inducer molecules that control gene circuits, which then can alter gene circuit function...
2018: Methods in Molecular Biology
Xiaoxiao Zhang, Yizhi Zhang, Fang Wang, Chong Wang, Lijiang Chen, Haiyang Liu, Hong Lu, Hong Wen, Tieli Zhou
To investigate the mechanisms of nitrofurantoin resistance and epidemiological characteristics in E. coli clinical isolates, 18 (1.2%, 18/1444) nitrofurantoin-resistant E. coli strains were identified from a total of 1444 E. coli clinical strains collected from our hospital. The present study indicated that the minimum inhibitory concentration of nitrofurantoin to nitrofurantoin-resistant strains were in a range of 128 - ≥512 μg /ml. The prevalence of nfsA gene in resistant, intermediate and sensitive strains were 88...
May 9, 2018: International Journal of Antimicrobial Agents
Cícera Datiane de Morais Oliveira-Tintino, Saulo Relison Tintino, Paulo W Limaverde, Fernando G Figueredo, Fábia F Campina, Francisco A B da Cunha, Roger H S da Costa, Pedro Silvino Pereira, Luciene F Lima, Yedda M L S de Matos, Henrique Douglas Melo Coutinho, José P Siqueira-Júnior, Valdir Q Balbino, Teresinha Gonçalves da Silva
This study was carried out to test the essential oil from C. ambrosioides leaves and its main constituent, α-Terpinene, in an antibacterial activity assay. As well, it was evaluated ability reduce resistance to norfloxacin and ethidium bromide was compared the Staphylococcus aureus 1199B whith 1199 wild type strain. The MIC of the C. ambrosioides essential oil and α-Terpinene were determined by microdilution method. The MIC of the essential oil and α-Terpinene presented a value ≥ 1024 μg/mL. However, when associated with antibacterials, the essential oil from C...
October 1, 2018: Food Chemistry
Felise G Adams, Uwe H Stroeher, Karl A Hassan, Shashikanth Marri, Melissa H Brown
In recent years, effective treatment of infections caused by Acinetobacter baumannii has become challenging due to the ability of the bacterium to acquire or up-regulate antimicrobial resistance determinants. Two component signal transduction systems are known to regulate expression of virulence factors including multidrug efflux pumps. Here, we investigated the role of the AdeRS two component signal transduction system in regulating the AdeAB efflux system, determined whether AdeA and/or AdeB can individually confer antimicrobial resistance, and explored the interplay between pentamidine resistance and growth conditions in A...
2018: PloS One
Zhaolin Chen, Cheng Huang, Taotao Ma, Ling Jiang, Liqin Tang, Tianlu Shi, Shantang Zhang, Lei Zhang, Pengli Zhu, Jun Li, Aizong Shen
BACKGROUND: Chemotherapy has been widely used to treat cancer, but the appearance of multidrug resistance (MDR) is the biggest obstacle to successful chemotherapy. One of the conventional mechanisms of MDR is overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp/ABCB1) and multidrug resistance-associated proteins (MRPs/ABCCs) that limits the prolonged and efficient use of chemotherapeutic drugs. To enhance the chemosensitivity of tumor cells, attentions have been focused on effective MDR modulators...
April 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Li Yang, Manjun Li, Fang Wang, Chen Zhen, Min Luo, Xiaona Fang, Hong Zhang, Jianye Zhang, Qingshan Li, Liwu Fu
BACKGROUND/AIMS: Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporters, such as ABCB1, ABCC1, and ABCG2, is a key obstacle for successful cancer chemotherapy. There is currently no FDA-approved MDR modulator that can be used in clinic. Ceritinib, a selective ALK inhibitor, has been approved as the second-line treatment for ALK-positive non-small cell lung cancer. Here, we examined the role of ceritinib in leukemia associated MDR in therapy. METHODS: The cell proliferation was detected by MTT assay...
May 5, 2018: Cellular Physiology and Biochemistry
Shahul Hameed P, Nagakumar Bharatham, Nainesh Katagihallimath, Sreevalli Sharma, Radha Nandishaiah, Anirudh P Shanbhag, Teby Thomas, Riya Narjari, Maitrayee Sarma, Purnendu Bhowmik, Prakruthi Amar, Rajani Ravishankar, Ramesh Jayaraman, Kubendran Muthan, Ramesh Subbiah, Vasanthi Ramachandran, V Balasubramanian, Santanu Datta
The mechanism of efflux is a tour-de-force in the bacterial armoury that has thwarted the development of novel antibiotics. We report the discovery of a novel chemical series with potent antibacterial properties that was engineered to overcome efflux liability. Compounds liable to efflux specifically via the Resistance Nodulation and cell Division (RND) pump, AcrAB-TolC were chosen for a hit to lead progression. Using structure-based design, the compounds were optimised to lose their binding to the efflux pump, thereby making them potent on wild-type bacteria...
May 8, 2018: Scientific Reports
Li-Min Wang, Ming-Yuan Zhang, Qiu-Shuang Zhu, Chun-Feng Lu, Xue Bai
BACKGROUND: Long-term chemotherapy reduces the sensitivity of colon cancer cells to chemotherapeutics like vincristine (VCR) and lead to drug resistance, which has become a major barrier for colon cancer treatment. Calcium antagonists are used as clinical tumor multidrug resistance reversal agents to regulate the P-glycoprotein (P-gp) level and block efflux pump function now, but they have significant side effects. Hyperin as active component with low toxicity in traditional Chinese medicine has calcium antagonistic effect...
March 1, 2018: Clinical Laboratory
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