致病菌中的藥物外排幫浦 (efflux pump) 會將抗生素排出體外降低藥物在菌體內的濃度，造成治療上的困難。而外排幫浦抑制劑 (efflux pump inhibitor, EPI) 能夠阻止外排幫浦外排抗生素並增強細菌對多種抗生素敏感性。本研究使用植物中常見的類黃酮 (apigenin, chrysin, glycitein 及 hesperetin) 與四種抗生素(ciprofloxacin, clarithromycin, erythromycin 及 tetracycline) 在不同濃度下進行協同性試驗發現四種類黃酮待測物至多能降兩倍的克拉黴素在Escherichia coli AcrAB-TolC 使用濃度。以螢光累積試驗及外排幫浦抑制試驗能夠發現 apigenin 及 hesperetin 可以抑制 AcrB 使螢光染劑溴化乙錠在菌株中的含量增加。透過細胞膜完整性試驗得知四種類黃酮對菌體不會破壞內膜，而在殺菌效力評估試驗上觀察到 apigenin 能夠提高克拉黴素 1/2 MIC 的抑菌效果；抗生素後效應試驗中可得知四種類黃酮皆無法明顯延長克拉黴素使用量；在生物膜抑制實驗上可以觀察到 apigenin, chrysin 及 glycitein 能抑制生物膜生成；藉由分子對接實驗的結果發現 apigenin 及 hesperetin 會與 distal binding pocket 以疏水性鍵結作用。
綜合上述可得知 apigenin 及 hesperetin 能夠對 AcrB 有抑制效果，能夠以此為基本結構做後續修飾，並成為有價值的 EPI。

The drug efflux pumps can translocate antibiotics to the extracelluar space, making it one of the most importnat drug resistance mechanisms. The efflux pump inhibitor (EPI) can inhibit the efflux pump, making it a promising adjunctive therapy. The objective of this study served to evaluate the EPI activity of the four flavonoids, apigenin, chrysin, glycitein and hesperetin for the E. coli drug efflux pump AcrB. In the modulation test, ciprofloxacin, clarithromycin, erythromycin and tetracycline were able to enhance the activity of clarithromycin to at least 2-fold. In the EtBr accumulation assay and efflux assay, apigenin or hesperetin were shown to increase the EB accumulation and reduce the EB efflux. The inner membrane permeabilisation assay indicated that the effects of the four flavonoids on the inner membranes were limited. In the time-kill assay, it was observed that apigenin can potentiate the clarithromycin activity. In the post-antibiotic effect assay, none of the four flavonoids could extend the growth time of the target bacteria after clarithromycin removal. In the biofilm inhibition experiment, it was observed that apigenin, chrysin and glycitein could inhibit the formation of biofilm. The results of the molecular docking experiment showed that apigenin and hesperetin could interact with the distal binding pocket in AcrB via hydrogen or nonconvalent bondings. To sum up, apigenin and hesperetin showed inhibitory activities against AcrB, making them promising EPI candidates, and subsequent modifications based on their structures might generate more efficient EPIs.

謝誌 I
摘要 I
縮寫表 VIII
壹、 前言 1
貳、 文獻整理 2
2.1 抗生素與抗藥性 2
2.1.1 抗生素的抗性機制 2
2.1.2 多重抗藥性 (Multidrug resistance, MDR) 4
2.1.3 細菌獲得抗藥性遺傳機制 5
2.1.4 抗藥性細菌的抗藥機制 6
2.2 抗藥性細菌轉運蛋白 (MDR efflux pump) 8
2.2.1 抗藥性細菌轉運蛋白簡介 8
2.2.2 多重抗藥性細菌轉運蛋白分類 9
2.2.3 RND轉運蛋白 10
2.2.4 E. coli 的 AcrAB-TolC 蛋白 11
2.2.5 AcrB 轉運蛋白及其運作機制 12
2.3 外排幫浦抑制劑 15
2.3.1 外排幫浦抑制劑簡介 15
2.3.2 外排幫浦抑制劑的來源及其常見的官能基 17
2.3.3 轉運幫浦抑制劑的篩選方法 20
2.4 植物中的外排幫浦抑制劑 22
2.4.1 植物中的 EPI 22
2.4.2 類黃酮 (flavonoids) 24
2.4.3 待測化合物簡介 26
參、 實驗設計 29
肆、 材料與方法 30
4.1 實驗材料 30
4.1.1 基因來源 30
4.1.2 菌體與質體 30
4.1.3 引子對 30
4.1.4 培養基 31
4.1.5 反應緩衝液 31
4.1.6 抗生素 31
4.1.7 化學藥品 32
4.1.8 實驗儀器與耗材 32
4.2. 實驗方法 33
4.2.1 藥物及待測化合物 33
4.2.2 菌株活化 33
4.2.2. 最小抑制濃度試驗 (MIC) 33
4.2.3. 協同殺菌試驗 (modulation assay) 34
4.2.4. 螢光累積試驗 (accumulation assay) 34
4.2.5 基質輔助雷射脫附游離/飛行時間質譜法 (Matrix-assisted laser desorption ionization time-of-flight mass spectrometry, MALDI-TOF MS) 34
4.2.6 外排抑制試驗 (efflux inhibition assay) 35
4.2.7 殺菌效力評估試驗 (time-kill assay) 35
4.2.8 細胞內膜完整性試驗 (inner membrane permeabilisation assay vs ONPG uptake assay) 36
4.2.9 結晶紫方法的生物膜試驗 (biofilm bilmass of crystal violet assay) 36
4.2.10 抗生素後效應試驗 (post-antibiotic effect assay) 37
4.2.11 分子對接試驗 (molecular docking) 37
伍、 結果 38
5.1 化合物與抗生素對具有抗藥性大腸桿菌之協同殺菌試驗 38
5.2 化合物對具有抗藥性大腸桿菌之螢光累積試驗 39
5.3 MALDI-TOF MS 40
5.4 外排抑制試驗 40
5.5 細胞內膜通透試驗 41
5.6 生物膜抑制試驗 42
5.7 殺菌效力評估試驗 43
5.8 抗生素後效應試驗 44
5.9 分子對接模型 44
陸、 結論 46
柒、 參考文獻 47

Abreu, A. C., Coqueiro, A., Sultan, A. R., Lemmens, N., Kim, H. K., Verpoorte, R., van Wamel, W. J. B., Simoes, M., & Choi, Y. H. (2017). Looking to nature for a new concept in antimicrobial treatments: Isoflavonoids from Cytisus striatus as antibiotic adjuvants against MRSA. Scientific Reports, 7.
Adamczak, A., Ozarowski, M., & Karpinski, T. M. (2020). Antibacterial activity of some flavonoids and organic acids widely distributed in plants. Journal of Clinical Medicine, 9, 109.
Akilandeswari, K., & Ruckmani, K. (2016). Synergistic antibacterial effect of apigenin with beta-lactam antibiotics and modulation of bacterial resistance by a possible membrane effect against methicillin resistant Staphylococcus aureus. Cellular and Molecular Biology, 62, 74-82.
Al-Anazi, A. F., Qureshi, V. F., Javaid, K., & Qureshi, S. (2011). Preventive effects of phytoestrogens against postmenopausal osteoporosis as compared to the available therapeutic choices: An overview. Journal of Natural Science, Biology and Medicine, 2, 154-163.
Alav, I., Sutton, J. M., & Rahman, K. M. (2018). Role of bacterial efflux pumps in biofilm formation. Journal of Antimicrobial Chemotherapy, 73, 2003-2020.
Aparna, V., Dineshkumar, K., Mohanalakshmi, N., Velmurugan, D., & Hopper, W. (2014). Identification of natural compound inhibitors for multidrug efflux pumps of Escherichia coli and Pseudomonas aeruginosa using in silico high-throughput virtual screening and in vitro validation. Plos One, 9, e101840.
Aranganathan, S., & Nalini, N. (2013). Antiproliferative efficacy of hesperetin (citrus flavanoid) in 1,2-dimethylhydrazine-Induced colon cancer. Phytotherapy Research, 27, 999-1005.
Aron, Z., & Opperman, T. J. (2018). The hydrophobic trap-the Achilles heel of RND efflux pumps. Research in Microbiology, 169, 393-400.
Arora, A., Nair, M. G., & Strasburg, G. M. (1998). Antioxidant activities of isoflavones and their biological metabolites in a liposomal system. Archives of Biochemistry and Biophysics, 356, 133-141.
Babiker, H. A., Pringle, S. J., Abdel-Muhsin, A., Mackinnon, M., Hunt, P., & Walliker, D. (2001). High-level chloroquine resistance in sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance gene pfmdr1. Journal of Infectious Diseases, 183, 1535-1538.
Batra, P., & Sharma, A. K. (2013). Anti-cancer potential of flavonoids: Recent trends and future perspectives. 3 Biotech, 3, 439-459.
Bay, D. C., Rommens, K. L., & Turner, R. J. (2008). Small multidrug resistance proteins: A multidrug transporter family that continues to grow. Biochimica Et Biophysica Acta-Biomembranes, 1778, 1814-1838.
Bay, D. C., & Turner, R. J. (2009). Diversity and evolution of the small multidrug resistance protein family. Bmc Evolutionary Biology, 9, 1-27.
Belhan, S., Yildirim, S., Karasu, A., Komuroglu, A. U., & Ozdek, U. (2020). Investigation of the protective role of chrysin within the framework of oxidative and inflammatory markers in experimental testicular ischaemia/reperfusion injury in rats. Andrologia, 52.
Biharee, A., Sharma, A., Kumar, A., & Jaitak, V. (2020). Antimicrobial flavonoids as a potential substitute for overcoming antimicrobial resistance. Fitoterapia, 146, 104720.
Blair, J. M. A., Webber, M. A., Baylay, A. J., Ogbolu, D. O., & Piddock, L. J. V. (2015). Molecular mechanisms of antibiotic resistance. Nature Reviews Microbiology, 13, 42-51.
Blanco, P., Hernando-Amado, S., Reales-Calderon, J. A., Corona, F., Lira, F., Alcalde-Rico, M., Bernardini, A., Sanchez, M. B., & Martinez, J. L. (2016). Bacterial multidrug efflux pumps: Much more than antibiotic resistance determinants. Microorganisms, 4, 14.
Bortolotto, V. C., Araujo, S. M., Pinheiro, F. C., Poetini, M. R., de Paula, M. T., Meichtry, L. B., de Almeida, F. P., Musachio, E. A. S., Guerra, G. P., & Prigol, M. (2020). Modulation of glutamate levels and Na+, K+- ATPase activity contributes to the chrysin memory recovery in hypothyroidism mice. Physiology & Behavior, 222, 112892.
Brown, A. R., Ettefagh, K. A., Todd, D., Cole, P. S., Egan, J. M., Foil, D. H., Graf, T. N., Schindler, B. D., Kaatz, G. W., & Cech, N. B. (2015). A mass spectrometry-based assay for improved quantitative measurements of efflux pump inhibition. Plos One, 10.
Cai, H. L., Rose, K., Liang, L. H., Dunham, S., & Stover, C. (2009). Development of a liquid chromatography/mass spectrometry-based drug accumulation assay in Pseudomonas aeruginosa. Analytical Biochemistry, 385, 321-325.
Cannon, R. D., Lamping, E., Holmes, A. R., Niimi, K., Baret, P. V., Keniya, M. V., Tanabe, K., Niimi, M., Goffeau, A., & Monk, B. C. (2009). Efflux-mediated antifungal drug resistance. Clinical Microbiology Reviews, 22, 291–321.
Cappelletty, D. M., & Rybak, M. J. (1996). Comparison of methodologies for synergism testing of drug combinations against resistant strains of Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, 40, 677-683.
Carter, E. L., Jager, L., Gardner, L., Hall, C. C., Willis, S., & Green, J. M. (2007). Escherichia coli abg genes enable uptake and cleavage of the folate catabolite p-aminobenzoyl-glutamate. Journal of Bacteriology, 189, 3329-3334.
Cavallini, D. C. U., Suzuki, J. Y., Abdalla, D. S. P., Vendramini, R. C., Pauly-Silveira, N. D., Roselino, M. N., Pinto, R. A., & Rossi, E. A. (2011). Influence of a probiotic soy product on fecal microbiota and its association with cardiovascular risk factors in an animal model. Lipids in Health and Disease, 10, 1-9.
Chambers, H. F., & Deleo, F. R. (2009). Waves of resistance: Staphylococcus aureus in the antibiotic era. Nature Reviews Microbiology, 7, 629-641.
Chan, B. C. L., Ip, M., Lau, C. B. S., Lui, S. L., Jolivalt, C., Ganem-Elbaz, C., Litaudon, M., Reiner, N. E., Gong, H. S., See, R. H., Fung, K. P., & Leung, P. C. (2011). Synergistic effects of baicalein with ciprofloxacin against NorA over-expressed methicillin-resistant Staphylococcus aureus (MRSA) and inhibition of MRSA pyruvate kinase. Journal of Ethnopharmacology, 137, 767-773.
Chen, H., Li, L., Liu, Y. Y., Wu, M. M., Xu, S. L., Zhang, G. J., Qi, C. F., Du, Y., Wang, M. L., Li, J. B., & Huang, X. H. (2018). In vitro activity and post-antibiotic effects of linezolid in combination with fosfomycin against clinical isolates of Staphylococcus aureus. Infection and Drug Resistance, 11, 2107-2115.
Chopra, I., & Roberts, M. (2001). Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiology and Molecular Biology Reviews, 65, 232-260.
Coldham, N. G., Webber, M., Woodward, M. J., & Piddock, L. J. V. (2010). A 96-well plate fluorescence assay for assessment of cellular permeability and active efflux in Salmonella enterica serovar Typhimurium and Escherichia coli. Journal of Antimicrobial Chemotherapy, 65, 1655-1663.
Connell, S. R., Tracz, D. M., Nierhaus, K. H., & Taylor, D. E. (2003). Ribosomal protection proteins and their mechanism of tetracycline resistance. Antimicrobial Agents and Chemotherapy, 47, 3675-3681.
Cushnie, T. P. T., Hamilton, V. E. S., Chapman, D. G., Taylor, P. W., & Lamb, A. J. (2007). Aggregation of Staphylococcus aureus following treatment with the antibacterial flavonol galangin. Journal of Applied Microbiology, 103, 1562-1567.
Delmar, J. A., & Yu, E. W. (2016). The AbgT family: A novel class of antimetabolite transporters. Protein Science, 25, 322-337.
Diniz-Silva, H. T., Magnani, M., de Siqueira, S., de Souza, E. L., & de Siqueira, J. P. (2017). Fruit flavonoids as modulators of norfloxacin resistance in Staphylococcus aureus that overexpresses norA. Lwt-Food Science and Technology, 85, 324-326.
Dixon, R. A., & Steele, C. L. (1999). Flavonoids and isoflavonoids - a gold mine for metabolic engineering. Trends Plant Science, 4, 394-400.
Drlica, K., Hiasa, H., Kerns, R., Malik, M., Mustaev, A., & Zhao, X. L. (2009). Quinolones: Action and resistance updated. Current Topics in Medicinal Chemistry, 9, 981-998.
Du, D. J., Wang, Z., James, N. R., Voss, J. E., Klimont, E., Ohene-Agyei, T., Venter, H., Chiu, W., & Luisi, B. F. (2014). Structure of the AcrAB-TolC multidrug efflux pump. Nature, 509, 512-515.
Dzidic, S., Suskovic, J., & Kos, B. (2008). Antibiotic resistance mechanisms in bacteria: Biochemical and genetic aspects. Food Technology and Biotechnology, 46, 11-21.
Eberhardt, J., Santos-Martins, D., Tillack, A. F., & Forli, S. (2021). AutoDock Vina 1.2.0: New docking methods, expanded force field, and Python bindings. Journal of Chemical Information and Modeling, 61, 3891-3898.
Elkins, C. A., & Mullis, L. B. (2006). Mammalian steroid hormones are substrates for the major RND- and MFS-type tripartite multidrug efflux pumps of Escherichia coli. Journal of Bacteriology, 188, 1191-1195.
Elkins, C. A., & Nikaido, H. (2002). Substrate specificity of the RND-type multidrug efflux pumps AcrB and AcrD of Escherichia coli is determined predominately by two large periplasmic loops. Journal of Bacteriology, 184, 6490-6498.
Elkins, C. A., & Nikaido, H. (2003). Chimeric analysis of AcrA function reveals the importance of its c-terminal domain in its interaction with the AcrB multidrug efflux pump. Journal of Bacteriology, 185, 5349-5356.
Epand, R. M., Walker, C., Epand, R. F., & Magarvey, N. A. (2016). Molecular mechanisms of membrane targeting antibiotics. Biochimica Et Biophysica Acta-Biomembranes, 1858, 980-987.
Fadli, M., Chevalier, J., Hassani, L., Mezrioui, N. E., & Pages, J. M. (2014). Natural extracts stimulate membrane-associated mechanisms of resistance in Gram-negative bacteria. Letters in Applied Microbiology, 58, 472-477.
Fawe, A., Abou-Zaid, M., Menzies, J. G., & Belanger, R. R. (1998). Silicon-mediated accumulation of flavonoid phytoalexins in cucumber. Phytopathology, 88, 396-401.
Felicetti, T., Mangiaterra, G., Cannalire, R., Cedraro, N., Pietrella, D., Astolfi, A., Massari, S., Tabarrini, O., Manfroni, G., Barreca, M. L., Cecchetti, V., Biavasco, F., & Sabatini, S. (2020). C-2 phenyl replacements to obtain potent quinoline-based Staphylococcus aureus NorA inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 35, 584-597.
Fernandez-Villa, D., Aguilar, M. R., & Rojo, L. (2019). Folic acid antagonists: antimicrobial and immunomodulating mechanisms and applications. International Journal of Molecular Sciences, 20, 4996.
Fidelis, Q. C., Faraone, I., Russo, D., Catunda, F. E. A., Vignola, L., de Carvalho, M. G., de Tommasi, N., & Milella, L. (2019). Chemical and biological insights of Ouratea hexasperma (A. St.-Hil.) Baill.: A source of bioactive compounds with multifunctional properties. Natural Product Research, 33, 1500-1503.
Fitzpatrick, A. W. P., Llabres, S., Neuberger, A., Blaza, J. N., Bai, X. C., Okada, U., Murakami, S., van Veen, H. W., Zachariae, U., Scheres, S. H. W., Luisi, B. F., & Du, D. J. (2017). Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump. Nature Microbiology, 2, 1-8.
Floss, H. G., & Yu, T. W. (2005). Rifamycin-mode of action, resistance, and biosynthesis. Chemical Reviews, 105, 621-632.
Fournier, B., Zhao, X. L., Lu, T., Drlica, K., & Hooper, D. C. (2000). Selective targeting of topoisomerase IV and DNA gyrase in Staphylococcus aureus: Different patterns of quinolone-induced inhibition of DNA synthesis. Antimicrobial Agents and Chemotherapy, 44, 2160-2165.
Gerber, A. U., & Craig, W. A. (1981). Growth kinetics of respiratory pathogens after short exposures to ampicillin and erythromycin in vitro. Journal of Antimicrobial Chemotherapy, 8 Suppl C, 81-91.
Gibbons, S., & Udo, E. E. (2000). The effect of reserpine, a modulator of multidrug efflux pumps, on the in vitro activity of tetracycline against clinical isolates of methicillin resistant Staphylococcus aureus (MRSA) possessing the tet(K) determinant. Phytotherapy Research, 14, 139-140.
Gillis, R. J., White, K. G., Choi, K. H., Wagner, V. E., Schweizer, H. P., & Iglewski, B. H. (2005). Molecular basis of azithromycin-resistant Pseudomonas aeruginosa biofilms. Antimicrobial Agents and Chemotherapy, 49, 3858-3867.
Gottesman, M. M., & Ling, V. (2006). The molecular basis of multidrug resistance in cancer: The early years of P-glycoprotein research. Febs Letters, 580, 998-1009.
Grundmann, H., Aires-De-Sousa, M., Boyce, J., & Tiemersma, E. (2006). Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet, 368, 874-885.
Hadjmohammadi, M. R., Saman, S., & Nazari, S. J. (2010). Separation optimization of quercetin, hesperetin and chrysin in honey by micellar liquid chromatography and experimental design. Journal of Separation Science, 33, 3144-3151.
Hartmann, G., Behr, W., Beissner, K. A., Honikel, K., & Sippel, A. (1968). Antibiotics as inhibitors of nucleic acid and protein synthesis. Angewandte Chemie International Edition, 7, 693-701.
Hassan, K. A., Elbourne, L. D. H., Li, L. P., Gamage, H. K. A. H., Liu, Q., Jackson, S. M., Sharples, D., Kolsto, A. B., Henderson, P. J. F., & Paulsen, I. T. (2015). An ace up their sleeve: A transcriptomic approach exposes the Acel efflux protein of Acinetobacter baumannii and reveals the drug efflux potential hidden in many microbial pathogens. Frontiers in Microbiology, 6, 333.
Hassan, K. A., Jackson, S. M., Penesyan, A., Patching, S. G., Tetu, S. G., Eijkelkamp, B. A., Brown, M. H., Henderson, P. J., & Paulsen, I. T. (2013). Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins. Proceedings of the National Academy of Sciences of the United States of America, 110, 20254-20259.
Henderson, P. J. F., Maher, C., Elbourne, L. D. H., Eijkelkamp, B. A., Paulsen, I. T., & Hassan, K. A. (2021). Physiological functions of bacterial "Multidrug" efflux pumps. Chemical Reviews, 121, 5417-5478.
Herrmann, F., & Wink, M. (2011). Synergistic interactions of saponins and monoterpenes in HeLa cells, Cos7 cells and in erythrocytes. Phytomedicine, 18, 1191-1196.
Higgins, C. F. (2007). Multiple molecular mechanisms for multidrug resistance transporters. Nature, 446, 749-757.
Holler, J. G., Christensen, S. B., Slotved, H. C., Rasmussen, H. B., Guzman, A., Olsen, C. E., Petersen, B., & Molgaard, P. (2012). Novel inhibitory activity of the Staphylococcus aureus NorA efflux pump by a kaempferol rhamnoside isolated from Persea lingue Nees. Journal of Antimicrobial Chemotherapy, 67, 1138-1144.
Holmes, A. H., Moore, L. S. P., Sundsfjord, A., Steinbakk, M., Regmi, S., Karkey, A., Guerin, P. J., & Piddock, L. J. V. (2016). Understanding the mechanisms and drivers of antimicrobial resistance. Lancet, 387, 176-187.
Husain, F., Bikhchandani, M., & Nikaido, H. (2011). Vestibules are part of the substrate path in the multidrug efflux transporter AcrB of Escherichia coli. Journal of Bacteriology, 193, 5847-5849.
Husain, F., & Nikaido, H. (2010). Substrate path in the AcrB multidrug efflux pump of Escherichia coli. Molecular Microbiology, 78, 320-330.
Hutchings, M. I., Truman, A. W., & Wilkinson, B. (2019). Antibiotics: past, present and future. Current Opinion in Microbiology, 51, 72-80.
Hwang, D., & Lim, Y. H. (2019). Resveratrol controls Escherichia coli growth by inhibiting the AcrAB-TolC efflux pump. Fems Microbiology Letters, 366, fnz030.
Jacqueline, C., Navas, D., Batard, E., Miegeville, A. F., Le Mabecque, V., Kergueris, M. F., Bugnon, D., Potel, G., & Caillon, J. (2005). In vitro and in vivo synergistic activities of linezolid combined with subinhibitory concentrations of imipenem against methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 49, 45-51.
Jang, S. (2016). Multidrug efflux pumps in Staphylococcus aureus and their clinical implications. Journal of Microbiology, 54, 1-8.
Jansen, M. A. K., van den Noort, R. E., Tan, M. Y. A., Prinsen, E., Lagrimini, L. M., & Thorneley, R. N. F. (2001). Phenol-oxidizing peroxidases contribute to the protection of plants from ultraviolet radiation stress. Plant Physiology, 126, 1012-1023.
Kaatz, G. W., Moudgal, V. V., Seo, S. M., & Kristiansen, J. E. (2003). Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 47, 719-726.
Kalia, N. P., Mahajan, P., Mehra, R., Nargotra, A., Sharma, J. P., Koul, S., & Khan, I. A. (2012). Capsaicin, a novel inhibitor of the NorA efflux pump, reduces the intracellular invasion of Staphylococcus aureus. Journal of Antimicrobial Chemotherapy, 67, 2401-2408.
Kalogeropoulos, N., Yanni, A. E., Koutrotsios, G., & Aloupi, M. (2013). Bioactive microconstituents and antioxidant properties of wild edible mushrooms from the island of Lesvos, Greece. Food and Chemical Toxicology, 55, 378-385.
Kobayashi, N., Nishino, K., & Yamaguchi, A. (2001). Novel macrolide-specific ABC-type efflux transporter in Escherichia coli. Journal of Bacteriology, 183, 5639-5644.
Kobylka, J., Kuth, M. S., Mueller, R. T., Geertsma, E. R., & Pos, K. M. (2020). AcrB: a mean, keen, drug efflux machine. Annals of the New York Academy of Sciences, 1459, 38-68.
Kong, W. C., Ling, X. M., Chen, Y., Wu, X. L., Zhao, Z. Q., Wang, W. W., Wang, S. L., Lai, G. X., & Yu, Z. Y. (2020). Hesperetin reverses P-glycoprotein-mediated cisplatin resistance in DDP-resistant human lung cancer cells via modulation of the nuclear factor-kappa B signaling pathway. International Journal of Molecular Medicine, 45, 1213-1224.
Koronakis, V., Sharff, A., Koronakis, E., Luisi, B., & Hughes, C. (2000). Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export. Nature, 405, 914-919.
Kumar, S., Mukherjee, M. M., & Varela, M. F. (2013). Modulation of bacterial multidrug resistance efflux pumps of the major facilitator superfamily. International Journal of Bacteriology, 2013, 1-15.
Kvist, M., Hancock, V., & Klemm, P. (2008). Inactivation of efflux pumps abolishes bacterial biofilm formation. Applied and Environmental Microbiology, 74, 7376-7382.
Lalani, S., & Poh, C. L. (2020). Flavonoids as antiviral agents for enterovirus A71 (EV-A71). Viruses, 12, 184.
Lamut, A., Masic, L. P., Kikelj, D., & Tomasic, T. (2019). Efflux pump inhibitors of clinically relevant multidrug resistant bacteria. Medicinal Research Reviews, 39, 2460-2504.
Law, C. J., Maloney, P. C., & Wang, D. N. (2008). Ins and outs of major facilitator superfamily antiporters. Annual Review of Microbiology, 62, 289-305.
Lechner, D., Gibbons, S., & Bucar, F. (2008). Plant phenolic compounds as ethidium bromide efflux inhibitors in Mycobacterium smegmatis. Journal of Antimicrobial Chemotherapy, 62, 345-348.
Lee, E. J., Kang, M. K., Kim, Y. H., Kim, D. Y., Oh, H., Kim, S. I., Oh, S. Y., & Kang, Y. H. (2019). Dietary chrysin suppresses formation of actin cytoskeleton and focal adhesion in AGE-exposed mesangial cells and diabetic kidney: Role of autophagy. Nutrients, 11, 127.
Lee, J. H., Regmi, S. C., Kim, J. A., Cho, M. H., Yun, H., Lee, C. S., & Lee, J. (2011). Apple flavonoid phloretin Inhibits Escherichia coli O157:H7 biofilm formation and ameliorates colon inflammation in rats. Infection and Immunity, 79, 4819-4827.
Lee, M. D., Galazzo, J. L., Staley, A. L., Lee, J. C., Warren, M. S., Fuernkranz, H., Chamberland, S., Lomovskaya, O., & Miller, G. H. (2001). Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco, 56, 81-85.
Lewinson, O., Adler, J., Sigal, N., & Bibi, E. (2006). Promiscuity in multidrug recognition and transport: the bacterial MFS Mdr transporters. Molecular Microbiology, 61, 277-284.
Lewis, K. (2012). Recover the lost art of drug discovery. Nature, 485, 439-440.
Li, J., Hossain, M. S., Ma, H. C., Yang, Q. H., Gong, X. W., Yang, P., & Feng, B. L. (2020). Comparative metabolomics reveals differences in flavonoid metabolites among different coloured buckwheat flowers. Journal of Food Composition and Analysis, 85.
Li, X.-Z., Livermore, D. M., & Nikaido, H. (1994). Role of efflux pump (s) in intrinsic resistance of Pseudomonas aeruginosa: Resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrobial Agents Chemotherapy, 38, 1732-1741.
Li, X. Z., Plesiat, P., & Nikaido, H. (2015). The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clinical Microbiology Reviews, 28, 337-418.
Lim, R., Barker, G., Wall, C. A., & Lappas, M. (2013). Dietary phytophenols curcumin, naringenin and apigenin reduce infection-induced inflammatory and contractile pathways in human placenta, foetal membranes and myometrium. Molecular Human Reproduction, 19, 451-462.
Lobedanz, S., Bokma, E., Symmons, M. F., Koronakis, E., Hughes, C., & Koronakis, V. (2007). A periplasmic coiled-coil interface underlying TolC recruitment and the assembly of bacterial drug efflux pumps. Proceedings of the National Academy of Sciences of the United States of America, 104, 4612-4617.
Lomovskaya, O., & Bostian, K. A. (2006). Practical applications and feasibility of efflux pump inhibitors in the clinic - A vision for applied use. Biochemical Pharmacology, 71, 910-918.
Lomovskaya, O., Warren, M. S., Lee, A., Galazzo, J., Fronko, R., Lee, M., Blais, J., Cho, D., Chamberland, S., Renau, T., Leger, R., Hecker, S., Watkins, W., Hoshino, K., Ishida, H., & Lee, V. J. (2001). Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: Novel agents for combination therapy. Antimicrobial Agents and Chemotherapy, 45, 105-116.
Lopes, L. A. A., dos Santos Rodrigues, J. B., Magnani, M., de Souza, E. L., & de Siqueira-Júnior, J. P. J. M. P. (2017). Inhibitory effects of flavonoids on biofilm formation by Staphylococcus aureus that overexpresses efflux protein genes. Microbial Pathogenesis, 107, 193-197.
Lopes, L. A. A., Rodrigues, J. B. D., Magnani, M., de Souza, E. L., & de Siqueira, J. P. (2017). Inhibitory effects of flavonoids on biofilm formation by Staphylococcus aureus that overexpresses efflux protein genes. Microbial Pathogenesis, 107, 193-197.
Lorenzi, V., Muselli, A., Bernardini, A. F., Berti, L., Pages, J. M., Amaral, L., & Bolla, J. M. (2009). Geraniol restores antibiotic activities against multidrug-resistant isolates from Gram-negative species. Antimicrobial Agents and Chemotherapy, 53, 2209-2211.
Lorian, V., Ernst, J., & Amaral, L. (1989). The post-antibiotic effect defined by bacterial morphology. J Antimicrob Chemother, 23, 485-491.
Lu, W. J., Huang, Y. J., Lin, H. J., Chang, C. J., Hsu, P. H., Ooi, G. X., Huang, M. Y., & Lin, H. T. V. (2022). Phenolic compound ethyl 3,4-dihydroxybenzoate retards drug efflux and potentiates antibiotic activity. Antibiotics-Basel, 11, 497.
Lu, W. J., Lin, H. J., Hsu, P. H., Lai, M., Chiu, J. Y., & Lin, H. T. V. (2019). Brown and red seaweeds serve as potential efflux pump inhibitors for drug-resistant Escherichia coli. Evidence-Based Complementary and Alternative Medicine, 2019.
Lu, W. J., Lin, H. J., Hsu, P. H., & Lin, H. T. V. (2020). Determination of drug efflux pump efficiency in drug-resistant bacteria using MALDI-TOF MS. Antibiotics-Basel, 9, 639.
Mahdhi, A., Leban, N., Chakroun, I., Bayar, S., Mahdouani, K., Majdoub, H., & Kouidhi, B. (2018). Use of extracellular polysaccharides, secreted by Lactobacillus plantarum and Bacillus spp., as reducing indole production agents to control biofilm formation and efflux pumps inhibitor in Escherichia coil. Microbial Pathogenesis, 125, 448-453.
Makela, S., Poutanen, M., Kostlan, M. L., Lehtimaki, N., Strauss, L., Santti, R., & Vihko, R. (1998). Inhibition of 17 beta-hydroxysteroid oxidoreductase by flavonoids in breast and prostate cancer cells. Proceedings of the Society for Experimental Biology and Medicine, 217, 310-316.
Mandalari, G., Bennett, R. N., Bisignano, G., Trombetta, D., Saija, A., Faulds, C. B., Gasson, M. J., & Narbad, A. (2007). Antimicrobial activity of flavonoids extracted from bergamot (Citrus bergamia Risso) peel, a byproduct of the essential oil industry. Journal of Applied Microbiology, 103, 2056-2064.
Marger, M. D., & Saier, M. H., Jr. (1993). A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport. Trends Biochem Science, 18, 13-20.
Markham, P. N., Westhaus, E., Klyachko, K., Johnson, M. E., & Neyfakh, A. A. (1999). Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 43, 2404-2408.
McMurry, L., Petrucci, R. E., Jr., & Levy, S. B. (1980). Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America, 77, 3974-3977.
Michalet, S., Cartier, G., David, B., Mariotte, A. M., Dijoux-Franca, M. G., Kaatz, G. W., Stavri, M., & Gibbons, S. (2007). N-Caffeoylphenalkylamide derivatives as bacterial efflux pump inhibitors. Bioorganic & Medicinal Chemistry Letters, 17, 1755-1758.
Mierziak, J., Kostyn, K., & Kulma, A. (2014). Flavonoids as important molecules of plant interactions with the environment. Molecules, 19, 16240-16265.
Mitchell, P. (1991). Foundations of vectorial metabolism and osmochemistry. Bioscience Reports, 11, 297-344; discussion 345-296.
Moir, J. W. B., & Wood, N. J. (2001). Nitrate and nitrite transport in bacteria. Cellular and Molecular Life Sciences, 58, 215-224.
Morel, C., Stermitz, F. R., Tegos, G., & Lewis, K. (2003). Isoflavones as potentiators of antibacterial activity. Journal of Agricultural and Food Chemistry, 51, 5677-5679.
Morita, Y., Kodama, K., Shiota, S., Mine, T., Kataoka, A., Mizushima, T., & Tsuchiya, T. (1998). NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli. Antimicrobial Agents and Chemotherapy, 42, 1778-1782.
Munita, J. M., & Arias, C. A. (2016). Mechanisms of antibiotic resistance. Microbiology Spectrum, 4, 2-4.
Murakami, S., Nakashima, R., Yamashita, E., Matsumoto, T., & Yamaguchi, A. (2006). Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature, 443, 173-179.
Murakami, S., Nakashima, R., Yamashita, E., & Yamaguchi, A. (2002). Crystal structure of bacterial multidrug efflux transporter AcrB. Nature, 419, 587-593.
Nagakubo, S., Nishino, K., Hirata, T., & Yamaguchi, A. (2002). The putative response regulator BaeR stimulates multidrug resistance of Escherichia coli via a novel multidrug exporter system, MdtABC. Journal of bacteriology, 184, 4161-4167.
Nakashima, R., Sakurai, K., Yamasaki, S., Hayashi, K., Nagata, C., Hoshino, K., Onodera, Y., Nishino, K., & Yamaguchi, A. (2013). Structural basis for the inhibition of bacterial multidrug exporters. Nature, 500, 102-U131.
Nakashima, R., Sakurai, K., Yamasaki, S., Nishino, K., & Yamaguchi, A. (2011). Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature, 480, 565-U199.
Neuberger, A., Du, D. J., & Luisi, B. E. (2018). Structure and mechanism of bacterial tripartite efflux pumps. Research in Microbiology, 169, 401-413.
Nies, D. H. (2003). Efflux-mediated heavy metal resistance in prokaryotes. Fems Microbiology Reviews, 27, 313-339.
Nikaido, H. (2009). Multidrug resistance in bacteria. Annual Review of Biochemistry, 78, 119-146.
Nikaido, H., & Takatsuka, Y. (2009). Mechanisms of RND multidrug efflux pumps. Biochimica Et Biophysica Acta-Proteins and Proteomics, 1794, 769-781.
Odds, F. C. (2003). Synergy, antagonism, and what the chequerboard puts between them. Journal of Antimicrobial Chemotherapy, 52, 1-1.
Olivares, J., Bernardini, A., Garcia-Leon, G., Corona, F., Sanchez, M. B., & Martinez, J. L. (2013). The intrinsic resistome of bacterial pathogens. Frontiers in Microbiology, 4, 103.
Oliveira-Tintino, C. D. D., Tintino, S. R., Limaverde, P. W., Figueredo, F. G., Campina, F. F., da Cunha, F. A. B., da Costa, R. H. S., Pereira, P. S., Lima, L. F., de Matos, Y. M. L. S., Coutinho, H. D. M., Siqueira, J. P., Balbino, V. Q., & da Silva, T. G. (2018). Inhibition of the essential oil from Chenopodium ambrosioides L. and alpha-terpinene on the NorA efflux-pump of Staphylococcus aureus. Food Chemistry, 262, 72-77.
Oluwatuyi, M., Kaatz, G. W., & Gibbons, S. (2004). Antibacterial and resistance modifying activity of Rosmarinus officinalis. Phytochemistry, 65, 3249-3254.
Opperman, T. J., Kwasny, S. M., Kim, H. S., Nguyen, S. T., Houseweart, C., D'Souza, S., Walker, G. C., Peet, N. P., Nikaido, H., & Bowlin, T. L. (2014). Characterization of a novel pyranopyridine Inhibitor of the AcrAB efflux pump of Escherichia coli. Antimicrobial Agents and Chemotherapy, 58, 722-733.
Opperman, T. J., & Nguyen, S. (2015). Recent advances toward a molecular mechanism of efflux pump inhibition. Frontiers in Microbiology, 6, 421.
Opperman, T. J., & Nguyen, S. T. (2015). Recent advances toward a molecular mechanism of efflux pump inhibition. Frontiers in Microbiology, 6, 421.
Ornano, L., Venditti, A., Donno, Y., Sanna, C., Ballero, M., & Bianco, A. (2016). Phytochemical analysis of non-volatile fraction of Artemisia caerulescens subsp densiflora (Viv.) (Asteraceae), an endemic species of La Maddalena Archipelago (Sardinia - Italy). Natural Product Research, 30, 920-925.
Oteiza, P. I., Erlejman, A. G., Verstraeten, S. V., Keen, C. L., & Fraga, C. G. (2005). Flavonoid-membrane interactions: A protective role of flavonoids at the membrane surface? Clinical and Developmental Immunology, 12, 19-25.
Pamp, S. J., Gjermansen, M., Johansen, H. K., & Tolker-Nielsen, T. (2008). Tolerance to the antimicrobial peptide colistin in Pseudomonas aeruginosa biofilms is linked to metabolically active cells, and depends on the pmr and mexAB-oprM genes. Molecular Microbiology, 68, 223-240.
Parhiz, H., Roohbakhsh, A., Soltani, F., Rezaee, R., & Iranshahi, M. (2015). Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: An updated review of their molecular mechanisms and experimental models. Phytotherapy Research, 29, 323-331.
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF chimera - A visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25, 1605-1612.
Pichichero, E., Cicconi, R., Mattei, M., Muzi, M. G., & Canini, A. (2010). Acacia honey and chrysin reduce proliferation of melanoma cells through alterations in cell cycle progression. International Journal of Oncology, 37, 973-981.
Poelarends, G. J., Mazurkiewicz, P., & Konings, W. N. (2002). Multidrug transporters and antibiotic resistance in Lactococcus lactis. Biochimica Et Biophysica Acta-Bioenergetics, 1555, 1-7.
Poole, K. (2005). Efflux-mediated antimicrobial resistance. Journal of Antimicrobial Chemotherapy, 56, 20-51.
Poole, K., Krebes, K., McNally, C., & Neshat, S. (1993). Multiple antibiotic resistance in Pseudomonas aeruginosa: Evidence for involvement of an efflux operon. Journal of Bacteriology, 175, 7363-7372.
Poolman, B., & Konings, W. N. (1993). Secondary solute transport in bacteria. Biochim Biophys Acta, 1183, 5-39.
Ramos, J. L., Duque, E., Gallegos, M. T., Godoy, P., Ramos-Gonzalez, M. I., Rojas, A., Teran, W., & Segura, A. (2002). Mechanisms of solvent tolerance in Gram-negative bacteria. Annual Review of Microbiology, 56, 743-768.
Rampioni, G., Pillai, C. R., Longo, F., Bondi, R., Baldelli, V., Messina, M., Imperi, F., Visca, P., & Leoni, L. (2017). Effect of efflux pump inhibition on Pseudomonas aeruginosa transcriptome and virulence. Scientific Reports, 7, 1-14.
Rand, K. H., Houck, H. J., Brown, P., & Bennett, D. (1993). Reproducibility of the microdilution checkerboard method for antibiotic synergy. Antimicrobial Agents and Chemotherapy, 37, 613-615.
Reis, R., & Moraes, I. (2019). Structural biology and structure-function relationships of membrane proteins. Biochemical Society Transactions, 47, 47-61.
Reygaert, W. C. (2018). An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiol, 4, 482-501.
Roccaro, A. S., Blanco, A. R., Giuliano, F., Rusciano, D., & Enea, V. (2004). Epigallocatechin-gallate enhances the activity of tetracycline in Staphylococci by inhibiting its efflux from bacterial cells. Antimicrobial Agents and Chemotherapy, 48, 1968-1973.
Ross, J. A., & Kasum, C. M. (2002). Dietary flavonoids: Bioavailability, metabolic effects, and safety. Annual Review of Nutrition, 22, 19-34.
Ross, R. (1993). The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature, 362, 801-809.
Roy, S. K., Kumari, N., Pahwa, S., Agrahari, U. C., Bhutani, K. K., Jachak, S. M., & Nandanwar, H. (2013). NorA efflux pump inhibitory activity of coumarins from Mesua ferrea. Fitoterapia, 90, 140-150.
Sanseverino, I., Navarro Cuenca, A., Loos, R., Marinov, D., & Lettieri, T. J. B. E. U. (2018). State of the art on the contribution of water to antimicrobial resistance.
Sassi, A., Boubaker, J., Loussaief, A., Jomaa, K., Ghedira, K., & Chekir-Ghedira, L. (2021). Protective effect of chrysin, a dietary flavone against genotoxic and oxidative damage induced by mitomycin C in Balb/C Mice. Nutrition and Cancer-an International Journal, 73, 329-338.
Sauvage, E., Kerff, F., Terrak, M., Ayala, J. A., & Charlier, P. (2008). The penicillin-binding proteins: Structure and role in peptidoglycan biosynthesis Fems Microbiology Reviews, 32, 556-556.
Scalbert, A., & Williamson, G. (2000). Dietary intake and bioavailability of polyphenols. Journal of Nutrition, 130, 2073s-2085s.
Schembri, M. A., Kjaergaard, K., & Klemm, P. (2003). Global gene expression in Escherichia coli biofilms. Molecular Microbiology, 48, 253-267.
Schweizer, H. P. (2012). Understanding efflux in gram-negative bacteria: Opportunities for drug discovery. Expert Opinion on Drug Discovery, 7, 633-642.
Seeger, M. A., Schiefner, A., Eicher, T., Verrey, F., Diederichs, K., & Pos, K. M. (2006). Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science, 313, 1295-1298.
Sennhauser, G., Amstutz, P., Briand, C., Storchenegger, O., & Grutter, M. G. (2007). Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. Plos Biology, 5, 106-113.
Seukep, A. J., Kuete, V., Nahar, L., Sarker, S. D., & Guo, M. Q. (2020). Plant-derived secondary metabolites as the main source of efflux pump inhibitors and methods for identification. Journal of Pharmaceutical Analysis, 10, 277-290.
Sharifi-Rad, M., Nazaruk, J., Polito, L., Morais-Braga, M. F. B., Rocha, J. E., Coutinho, H. D. M., Salehi, B., Tabanelli, G., Montanari, C., Contreras, M. D., Yousaf, Z., Setzer, W. N., Verma, D. R., Martorell, M., Sureda, A., & Sharifi-Rad, J. (2018). Matricaria genus as a source of antimicrobial agents: From farm to pharmacy and food applications. Microbiological Research, 215, 76-88.
Sharma, S., Kumar, M., Sharma, S., Nargotra, A., Koul, S., & Khan, I. A. (2010). Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis. Journal of Antimicrobial Chemotherapy, 65, 1694-1701.
Solnier, J., Martin, L., Bhakta, S., & Bucar, F. (2020). Flavonoids as novel efflux pump inhibitors and antimicrobials against both environmental and pathogenic intracellular Mycobacterial species. Molecules, 25, 734.
Soto, S. M. (2013). Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm. Virulence, 4, 223-229.
Stermitz, F. R., Lorenz, P., Tawara, J. N., Zenewicz, L. A., & Lewis, K. (2000). Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5 '-methoxyhydnocarpin, a multidrug pump inhibitor. Proceedings of the National Academy of Sciences of the United States of America, 97, 1433-1437.
Stompor-Goracy, M., Bajek-Bil, A., & Machaczka, M. (2021). Chrysin: Perspectives on contemporary status and future possibilities as pro-health agent. Nutrients, 13, 2038.
Stubbings, W., Bostock, J., Ingham, E., & Chopra, I. (2005). Deletion of the multiple-drug efflux pump AcrAB in Escherichia coli prolongs the postantibiotic effect. Antimicrobial Agents and Chemotherapy, 49, 1206-1208.
Sudarshan, N. R., Hoover, D. G., & Knorr, D. (1992). Antibacterial action of chitosan. Food Biotechnology, 6, 257-272.
Sugino, A., Higgins, N. P., Brown, P. O., Peebles, C. L., & Cozzarelli, N. R. (1978). Energy coupling in DNA gyrase and the mechanism of action of novobiocin. Proceedings of the National Academy of Sciences of the United States of America, 75, 4838-4842.
Symmons, M. F., Bokma, E., Koronakis, E., Hughes, C., & Koronakis, V. (2009). The assembled structure of a complete tripartite bacterial multidrug efflux pump. Proceedings of the National Academy of Sciences of the United States of America, 106, 7173-7178.
Tambat, R., Jangra, M., Mahey, N., Chandal, N., Kaur, M., Chaudhary, S., Verma, D. K., Thakur, K. G., Raje, M., Jachak, S., Khatri, N., & Nandanwar, H. (2019). Microbe-derived indole metabolite demonstrates potent multidrug efflux pump inhibition in Staphylococcus aureus. Frontiers in Microbiology, 10, 2153.
Tanabe, M., Szakonyi, G., Brown, K. A., Henderson, P. J., Nield, J., & Byrne, B. (2009). The multidrug resistance efflux complex, EmrAB from Escherichia coli forms a dimer in vitro. Biochemical and Biophysical Research Communications, 380, 338-342.
Tanaka, Y., Hipolito, C. J., Maturana, A. D., Ito, K., Kuroda, T., Higuchi, T., Katoh, T., Kato, H. E., Hattori, M., Kumazaki, K., Tsukazaki, T., Ishitani, R., Suga, H., & Nureki, O. (2013). Structural basis for the drug extrusion mechanism by a MATE multidrug transporter. Nature, 496, 247-251.
Vaez, H., Faghri, J., Isfahani, B. N., Moghim, S., Yadegari, S., Fazeli, H., Moghofeei, M., & Safaei, H. G. (2014). Efflux pump regulatory genes mutations in multidrug resistance Pseudomonas aeruginosa isolated from wound infections in Isfahan hospitals. Adv Biomed Res, 3, 117.
van Veen, H. W., & Konings, W. N. (1998). The ABC family of multidrug transporters in microorganisms. Biochimica et Biophysica Acta, 1365, 31-36.
Varela, M. F., Stephen, J., Lekshmi, M., Ojha, M., Wenzel, N., Sanford, L. M., Hernandez, A. J., Parvathi, A., & Kumar, S. H. (2021). Bacterial resistance to antimicrobial agents. Antibiotics-Basel, 10.
Vazquez-Laslop, N., & Mankin, A. S. (2018). How macrolide antibiotics work. Trends Biochemical Sciences, 43, 668-684.
Veal, W. L., & Shafer, W. M. (2003). Identification of a cell envelope protein (MtrF) involved in hydrophobic antimicrobial resistance in Neisseria gonorrhoeae. Journal of Antimicrobial Chemotherapy, 51, 27-37.
Venditti, A., Frezza, C., Sciubba, F., Serafini, M., Bianco, A., Cianfaglione, K., Lupidi, G., Quassinti, L., Bramucci, M., & Maggi, F. (2018). Volatile components, polar constituents and biological activity of tansy daisy (Tanacetum macrophyllum (Waldst. et Kit.) Schultz Bip.). Industrial Crops and Products, 118, 225-235.
Venditti, A., Maggi, F., Vittori, S., Papa, F., Serrilli, A. M., Di Cecco, M., Ciaschetti, G., Mandrone, M., Poli, F., & Bianco, A. (2015). Antioxidant and alpha-glucosidase inhibitory activities of Achillea tenorii. Pharmaceutical Biology, 53, 1505-1510.
Venter, H., Mowla, R., Ohene-Agyei, T., & Ma, S. (2015). RND-type drug efflux pumps from Gram-negative bacteria: Molecular mechanism and inhibition. Frontiers in Microbiology, 6, 377.
Vikram, A., Jayaprakasha, G. K., Jesudhasan, P. R., Pillai, S. D., & Patil, B. S. (2010). Suppression of bacterial cell-cell signalling, biofilm formation and type III secretion system by citrus flavonoids. Journal of Applied Microbiology, 109, 515-527.
Vila, J., & Martinez, J. L. (2008). Clinical impact of the over-expression of efflux pump in nonfermentative Gram-negative bacilli, development of efflux pump inhibitors. Current Drug Targets, 9, 797-807.
Villa-Rodriguez, J. A., Kerimi, A., Abranko, L., Tumova, S., Ford, L., Blackburn, R. S., Rayner, C., & Williamson, G. (2018). Acute metabolic actions of the major polyphenols in chamomile: An in vitro mechanistic study on their potential to attenuate postprandial hyperglycaemia. Scientific Reports, 8, 1-14.
Viveiros, M., Martins, A., Paixão, L., Rodrigues, L., Martins, M., Couto, I., Fähnrich, E., Kern, W. V., & Amaral, L. (2008). Demonstration of intrinsic efflux activity of Escherichia coli K-12 AG100 by an automated ethidium bromide method. International Journal of Antimicrobial Agents, 31, 458-462.
Wang, Y., Yi, L., Wang, Y. X., Wang, Y. G., Cai, Y., Zhao, W. P., & Ding, C. (2016). Isolation, phylogenetic group, drug resistance, biofilm formation, and adherence genes of Escherichia coli from poultry in central China. Poultry Science, 95, 2895-2901.
Wang, Z., Fan, G., Hryc, C. F., Blaza, J. N., Serysheva, I. I., Schmid, M. F., Chiu, W., Luisi, B. F., & Du, D. (2017). An allosteric transport mechanism for the AcrAB-TolC multidrug efflux pump. elife, 6, e24905.
Wasson, A. P., Pellerone, F. I., & Mathesius, U. (2006). Silencing the flavonoid pathway in Medicago truncatula inhibits root nodule formation and prevents auxin transport regulation by rhizobia. Plant Cell, 18, 1617-1629.
Weisblum, B. (1995). Erythromycin resistance by ribosome modification. Antimicrobial Agents and Chemotherapy, 39, 577-585.
White, R. L., Burgess, D. S., Manduru, M., & Bosso, J. A. (1996). Comparison of three different in vitro methods of detecting synergy: Time-kill, checkerboard, and E test. Antimicrobial Agents and Chemotherapy, 40, 1914-1918.
Whittle, E. E., Legood, S. W., Alav, I., Dulyayangkul, P., Overton, T. W., & Blair, J. M. A. (2019). Flow cytometric analysis of efflux by dye accumulation. Frontiers in Microbiology, 10.
Williams, C. A., & Grayer, R. J. (2004). Anthocyanins and other flavonoids. Natural Product Reports, 21, 539-573.
Wilson, D. N. (2009). The A-Z of bacterial translation inhibitors. Critical Reviews in Biochemistry and Molecular Biology, 44, 393-433.
Yamaguchi, A., Nakashima, R., & Sakurai, K. (2015). Structural basis of RND-type multidrug exporters. Frontiers in Microbiology, 6, 327.
Yamasaki, S., Nikaido, E., Nakashima, R., Sakurai, K., Fujiwara, D., Fujii, I., & Nishino, K. (2013). The crystal structure of multidrug-resistance regulator RamR with multiple drugs. Nature Communications, 4, 1-7.
Yamasaki, S., Wang, L. Y., Hirata, T., Hayashi-Nishino, M., & Nishino, K. (2015). Multidrug efflux pumps contribute to Escherichia coli biofilm maintenance. International Journal of Antimicrobial Agents, 45, 439-441.
Yang, Y., Wolfram, J., Boom, K., Fang, X. H., Shen, H. F., & Ferrari, M. (2013). Hesperetin impairs glucose uptake and inhibits proliferation of breast cancer cells. Cell Biochemistry and Function, 31, 374-379.
Yang, Y., Wolfram, J., Shen, H. F., Fang, X. H., & Ferrari, M. (2012). Hesperetin: An inhibitor of the transforming growth factor-beta (TGF-beta) signaling pathway. European Journal of Medicinal Chemistry, 58, 390-395.
Yao, J., Jiang, M. Z., Zhang, Y. S., Liu, X., Du, Q., & Feng, G. Z. (2016). Chrysin alleviates allergic inflammation and airway remodeling in a murine model of chronic asthma. International Immunopharmacology, 32, 24-31.
Yu, E. W., McDermott, G., Zgurskaya, H. I., Nikaido, H., & Koshland, D. E. (2003). Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science, 300, 976-980.
Zeng, B., Wang, H. N., Zou, L. K., Zhang, A. Y., Yang, X., & Guan, Z. B. (2010). Evaluation and target validation of indole derivatives as inhibitors of the AcrAB-TolC efflux pump. Bioscience Biotechnology and Biochemistry, 74, 2237-2241.
Zgurskaya, H. I., & Nikaido, H. (2000). Multidrug resistance mechanisms: Drug efflux across two membranes. Molecular Microbiology, 37, 219-225.
Zhang, L., & Mah, T. F. (2008). Involvement of a novel efflux system in biofilm-specific resistance to antibiotics. Journal of Bacteriology, 190, 4447-4452.
Zhou, X., Wang, F., Zhou, R. J., Song, X. M., & Xie, M. L. (2017). Apigenin: A current review on its beneficial biological activities. Journal of Food Biochemistry, 41, e12376.
Zhou, Z. W., Zhang, Y., Lin, L. N., & Zhou, J. M. (2018). Apigenin suppresses the apoptosis of H9C2 rat cardiomyocytes subjected to myocardial ischemia-reperfusion injury via upregulation of the PI3K/Akt pathway. Molecular Medicine Reports, 18, 1560-1570.
Zwama, M., & Yamaguchi, A. (2018). Molecular mechanisms of AcrB-mediated multidrug export. Research in Microbiology, 169, 372-383.
Zwama, M., Yamasaki, S., Nakashima, R., Sakurai, K., Nishino, K., & Yamaguchi, A. (2018). Multiple entry pathways within the efflux transporter AcrB contribute to multidrug recognition. Nature Communications, 9.