臺灣博碩士論文加值系統

背景：許多自然存在具有萘醌結構之天然化合物皆具有藥理活性，尤其容易激發產生活性氧分子，例如白花丹素（5-hydroxy-2-methyl-1,4-naphthoquinone）與指甲花醌（2-hydroxy-1,4-naphthoquinone），其皆具有抗發炎、抗細菌、抗黴菌、殺病毒、殺原蟲和抑制癌細胞的能力。而結核菌萘醌（2-hydroxy-3-methyl-1,4- naphthoquinone）則具有抗菌的能力。已知白花丹素處理大腸桿菌後對細菌具有毒殺能力，此時細菌會啟動抗藥機制，這個抗藥機制與ygfZ基因相關。目的：分析大腸桿菌對抗具有相同萘醌核心結構的天然化合物指甲花醌、結核菌萘醌與白花丹素之抗藥機制，並分析其中ygfZ基因啟動子之marbox高度保留序列所扮演角色以及上游轉錄因子之調控情形，同時了解mar/sox調控組之藥物排出幫浦AcrAB-TolC是否參與細菌對抗萘醌類化合物。材料與方法：本實驗利用報導基因實驗觀察marbox高度保留序列對於ygfZ promoter表現的重要性，同時利用轉錄因子ΔsoxS與ΔmarA的突變株來釐清此二轉錄因子與ygfZ啟動子活化的相關性。此外，以藥物排出幫浦抑制劑（phenylalanine arginine β-naphthylamid，PAβN）抑制排出幫浦功能以分析AcrAB-TolC對抗萘醌類藥物機制的重要性。結果與討論：指甲花醌、結核菌萘醌與白花丹素對於大腸桿菌皆有毒性，且在各藥物處理之下，皆會引起ygfZ大量表現以減少這三種萘醌類藥物的毒性。攜帶完整 ygfZ啟動子序列的組別比marbox突變之ygfZ啟動子對藥物的反應較大，可知marbox高度保留序列對ygfZ表現的重要性。在萘醌類藥物處理時若加入PAβN排出幫浦抑制劑，發現AcrAB-TolC排出幫浦對於抗萘醌類藥物有一定的重要性。然而，一旦缺乏ygfZ基因時，AcrAB-TolC卻無法消除萘醌類藥物對細菌的毒殺能力，可知ygfZ基因對萘醌類藥物抗性扮演主要角色。

Background: Many natural compounds with naphthoquinone structure, which are extremely easy to stimulate the generation of reactive oxygen species, and they are having pharmacological properties. For example: plumbagin (5-hydroxy- 2-methyl-1,4-naphthoquinone) and lawsone (2-hydroxy-1,4-naphthoquinone) are anti-inflammatory, antibacterial, antifungal, antiviral, antiprotozoan and anti-cancer capality, while phthiocol (2-hydroxy-3-methyl-1,4-naphthoquinone) is antibacterial. It has been known that plumbagin is very toxic to Escherichia coli (E. coli), which initiates the resistant mechanism associated with ygfZ gene when treated with plumbagin. Objective: The E. coli resistance mechanisms involved in the against to the natural naphthoquinone drugs, such as lawsone, phthiocol and plumbagin. The role of the highly conserved marbox region played in the naphthoquinone resistance, and the importance of the AcrAB-TolC efflux pump belonging to the mar/sox regulon were studied in the experiments. Materials and Methods: Using β-galactosidase gene reporter assay, the importance of the highly conserved marbox sequence in drug resistance mechanisms was demonstrated with a marbox mutant. Also, the relationship between the ygfZ promoter and two transcription factors SoxS and MarA was clarified. In addition, the drug efflux pump inhibitor phenylalanine arginine β-naphthylamid, (PAβN) was used to analyze the involvement of AcrAB-TolC in the drug resistance mechanism. Results and Discussion: Plumbagin, lawsone and phthiocol were toxic to E. coli, and E. coli upregulated ygfZ expression to decrease their toxicities. Bacteria containing the reporter with intact marbox region possessed higher ygfZ expression than the marbox mutant one during the drug treatments. It demonstrated that the highly conserved marbox is essential to ygfZ induction by naphthoquinones. AcrAB-TolC is evidenced important in drug resistance in E. coli when co-treated with naphthoquinones and the efflux pump inhibitor PAβN. However, AcrAB-TolC cannot eliminate the toxicity to E. coli in the lack of ygfZ. In conclusion, ygfZ plays the critical role in the naphthoquinone resistance of E. coli.

摘要 i
ABSTRACT ii
致謝 iv
目錄 v
表目錄 viii
圖目錄 ix
第一章 文獻回顧 1
第一節 大腸桿菌 (Escherichia coli) 1
1.1大腸桿菌血清型與致病毒素(E coli serotype and pathogenic toxins) ...1
1.2 腸道致病性大腸桿菌分型 (Types of pathogenic Escherichia coli in gastrointestinal tract) 2
1.3 尿原性大腸桿菌 (Uropathgenic Escherichia coli, UPEC) 3
1.4 新生兒腦膜炎大腸桿菌 (Neonatal meningitis Escherichia coli, NMEC) 3
第二節 萘醌類化合物 (Naphthoquinone compounds) 3
2.1 白花丹素 (Plumbagin) 5
2.2 指甲花醌 (Lawsone) 6
2.3 結核菌萘醌 (Phthiocol) 7

第三節 大腸桿菌對萘醌化合物之抗藥機制 7
3.1 mar/sox 調控組 8
3.2 marbox序列 9
3.3 抗萘醌類藥物機制 9
3.4 藥物排出幫浦 10
第二章 前言 12
第三章 材料與方法 14
第一節 菌株來源 14
第二節 藥物來源 14
第三節YGFZ報導基因質體之建構 14
3.1 抽取含ygfZ基因片段的質體 15
3.2 選殖並核酸定序ygfZ啟動子序列 16
3.3 ygfZ啟動子片段嵌入帶有完整lacZ報導基因載體pKM005中 18
第四節 目標質體轉入各種大腸桿菌菌株 22
4.1 製作勝任細胞與轉型作用 22
4.2檢測轉型菌株之質體 23
第五節 抗藥性試驗 23
5.1 最小抑菌濃度試驗（Minimum inhibitory concentration test） 23
5.2 紙錠試驗（Disc diffusion assay） 24

第六節 報導基因菌株之β-半乳糖活性試驗（β-galactosidase assay） 24
第七節 統計分析 25
第四章 結果 26
第一節 大腸桿菌菌株對各萘醌類化合物最小抑菌濃度分析 26
第二節 紙錠試驗確認大腸桿菌菌株對各萘醌類化合物敏感性 27
第三節 萘醌類化合物引致ygfZ啟動子活性變化之基因報導分析 28
3.1 marbox序列突變後對萘醌類化合物啟動ygfZ表現的重要性 29
3.2 SoxS與MarA轉錄活化因子對ygfZ啟動子marbox序列之調控 30
3.3 AcrAB-TolC藥物排出幫浦的重要性 33
第五章 結論 35
第六章 討論 36
參考文獻 39

1. 邢其毅（2005）。第19章，酚和醌。載於邢其毅、裴偉偉、徐瑞秋、裴堅，基礎有機化學，第三版（857-870頁）。北京：高等教育出版社。
2. 陳建安（2007）白花丹素抑制胰臟癌細胞生長的機轉探討。碩士論文。長庚大學。
3. 徐詩雯、郭仲恒、李峙樺、吳進益及王紹鴻（2011）體外試驗探討具不同功能基天然萘醌衍生物之抗菌與細胞毒殺效力。應用微生物學組壁報論文。第二十屆第二次會員大會暨學術研討會，台南市國立成功大學。
4. Alekshun M. N. &; S. B. Levy (1999) Alteration of the repressor activity of MarR, the negative regulator of the Escherichia coli marRAB locus, by multiple chemicals in vitro. Journal of Bacteriology 181: 4669–4672.
5. Alekshun M. N. &; S. B. Levy (1999) The mar regulon: multiple resistance to antibiotics and other toxic chemicals. Trends in Microbiology 7: 410-413.
6. Alekshun M. N. &; S. B. Levy (2007) Molecular mechanisms of antibacterial multidrug resistance. Cell 128:1037-1050.
7. Aono R, N. Tsukagoshi &; M. Yamamoto (1998) Involvement of outer membrane protein TolC, a possible member of the mar-sox regulon, in maintenance and improvement of organic solvent tolerance of Escherichia coli K-12. Journal of Bacteriology 180: 938–944.
8. Askoura M., W. Mattawa, T. Abujamel &; I. Taher (2011) Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa. Libyan Journal of Medicine 6: 5870.
9. Ball E. G. (1934) Studies on oxidation-reduction: xxi. phthiocol, the pigment of the human tubercle bacillus. Journal of Biological Chemistry 106: 515-524.
10. Ball E. G., C. B. Anfinsen &; O. Cooper (1947) The inhibitory action of naphthoquinones on respiratory processes. Journal of Biological Chemistry 168: 257-70.
11. Barbosa T. M. &; S. B. Levy (2000) Differential Expression of over 60 Chromosomal Genes in Escherichia coli by Constitutive Expression of MarA. Journal of Bacteriology 182: 3467–3474.
12. Barbosa T. M. &; S. B. Levy (2002) Activation of the Escherichia coli nfnB gene by MarA through a highly divergent marbox in a class II promoter. Molecular Microbology 45: 191-202.
13. Bollenbach T. &; R. Kishony (2011) Resolution of gene regulatory conflicts caused by combinations of antibiotics. Molecular Cell 42: 413–425.
14. Chen J. W., C. M. Sun, W. L. Sheng, Y. C. Wang &; W. J. Syu (2006) Expression analysis of up-regulated genes responding to plumbagin in Escherichia coli. Journal of Bacteriology 188: 456-463.
15. Chubiz L. M. &; Rao C.V. (2010) Aromatic acid metabolites of Escherichia coli K-12 can induce the marRAB operon. Journal of Bacteriology 192: 4786–4789.
16. Chubiz L. M &; Rao C. V. (2011) Role of the mar-sox-rob regulon in regulating outer membrane porin expression. Journal of Bacteriology 193: 2252–2260.
17. Cohen S. P., S. B. Levy, J. Foulds &; J. L. Rosner (1993) Salicylate induction of antibiotic resistance in Escherichia coli: activation of the mar operon and a mar-independent pathway. Journal of Bacteriology 175: 7856–7862.
18. Curreli N., F. Sollai, L. Massa, O. Comandini, A. Rufo, E. Sanjust, A. Rinaldi &; A. C. Rinaldi (2001) Effects of plant-derived naphthoquinones on the growth of Pleurotus sajor-caju and degradation of the compounds by fungal cultures. Journal of Basic Microbiology 5: 253-259.
19. de Paiva S. R., M. R. Figueiredo, T. V. Aragão &; M. A. Kaplan . (2003) Antimicrobial activity in vitro of plumbagin isolated from Plumbago species. Memórias do Instituto Oswaldo Cruz 98: 959-961.
20. Delvaeye M., M. Noris, A. De Vriese, C. T. Esmon, N. L. Esmon, G. Ferrell, J. Del-Favero, S. Plaisance, B. Claes, D. Lambrechts, C. Zoja, G. Remuzzi &; E. M. Conway. (2009) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. New England Journal Medicine 361: 345-357.
21. Donnenberg M. S., A. D. Rolfe &; G. T. Keusch (1989) Epithelial Cell Invasion: An overlooked property of enteropathogenic Escherichia coli (EPEC) associated with the EPEC adherence factor. Journal of Infection Disease160: 452-459.
22. Drusano G. L., S. L. Preston, C. Fowler, M. Corrado, B. Weisinger &; J. Kahn (2004) Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia. Journal of Infections Disease 189: 1590-1597.
23. Dubbs J. M. &; S. Mongkolsuk (2007) Peroxiredoxins in bacterial antioxidant defense. Sub-cellular Biochemistry 44: 143-193.
24. Firdausi Q., A. M. Svennerholm, A. S. G. Faruque &; R. B. Sack. (2005) Entrotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical features, treatment, and prevention. Clinical Microbiology Reviews 18: 465-483.
25. Fralick J.A. (1996) Evidence that TolC is required for functioning of the Mar/AcrAB efflux pump of Escherichia coli. Journal of Bacteriology 178:5803–5805.
26. Freytag L. C. &; J. D. Clements (1999) Bacterial toxins as mucosal adjuvants. Current Topics in Microbiology and Immunology 236: 215-236.
27. Gaffron H. (1945) Some effects of derivatives of vitamin k on the metabolism of unicellular algae. Journal of Cell Biology 20: 259-68.
28. Galhardo R. S., C. E. Almeida, A. C. Leitao &; J. B. Cabral-Neto (2000) Repair of DNA lesions induced by hydrogen peroxide in the presence of iron chelators in Escherichia coli: participation of endonuclease IV and Fpg. Journal of Bacteriology 182: 1964-1968.
29. Gardner P. R. (1996) Superoxide production by the mycobacterial and pseudomonad quinoid pigments phthiocol and pyocyanine in human lung cells. Archives of Biochemistry and Biophysics 333: 267-74.
30. Gaudu P. &; B. Weiss (1996) SoxR, a [2Fe-2S] transcription factor, is active only in its oxidized form. Proceedings of the National Acdemy of Science of USA 93: 10094-10098.
31. Glode M. P., A. Sutton , J. B. Robbins , G. H. McCracken , E. C. Gotschlich , B. Kaijser &; L. A. Hanson (1997) Neonatal meningitis due of Escherichia coli K1. Journal of Infection Disease 136: s93-97.
32. Griffith K. L., M. M. Fitzpatrick, E. F. Keen &; R. E. Wolf (2009). Two functions of the C-terminal domain of Escherichia coli Rob: mediating “sequestration-dispersal” as a novel off-on switch for regulating Rob's activity as a transcription activator and preventing degradation of Rob by Lon protease. Journal of Molecular Biology 388:415–430.
33. Hidalgo E &; B. Demple (1996) Activation of SoxR-dependent transcription in vitro by noncatalytic or NifS-mediated assembly of [2Fe-2S] clusters into apo-SoxR. Journal of Biological Chemistry 271:7269–7272.
34. Hidalgo E., J. M. Bollinger, T. M. Bradley, C. T. Walsh &; B. Demple (1995) Binuclear [2Fe-2S] clusters in the Escherichia coli SoxR protein and role of the metal centers in transcription. Journal of Biological Chemistry 270: 20908–20914.
35. Imlay J &; I. Fridovich (1992) Exogenous quinones directly inhibit the respiratory NADH dehydrogenase in Escherichia coli. Archives of Biochemistry and Biophysics 296: 337-346.
36. Iuchi S. &; L. Weiner (1996) Cellular and molecular physiology of Escherichia coli in the adaptation to aerobic environments. Journal of Biological Chemistry 120: 1055-1063.
37. Jair K. W., R. G. Martin, J. L. Rosner, N. Fujita, A. Ishihama &; R. E. Wolf (1995) Purification and regulatory properties of MarA protein, a transcriptional activator of Escherichia coli multiple antibiotic and superoxide resistance promoters. Journal of Bacteriology 177: 7100–7104.
38. Jair K. W., X. Yu, K. Skarstad, B. Thöny, N. Fujita, A. Ishihama &; R. E. Wolf (1996) Transcriptional activation of promoters of the superoxide and multiple antibiotic resistance regulons by Rob, a binding protein of the Escherichia coli origin of chromosomal replication. Journal of Bacteriology 178: 2507–2513.
39. Jeffrey H. Miller. Experiments in Molecular Genetics. Cold Spring Harbor Laboratory, 1972. ISBN: 0879691069.
40. Kaper J. B., J. P. Nataro &; H. L. Mobley (2004) Pathogenic Escherichia coli. Nature Reviews Microbiology 2: 123–140.
41. Kohanski M. A., D. J. Dwyer, B. Hayete, C. A. Lawrence &; J. J. Collins (2007) A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130:797–810.
42. Krishnaswamy, M. &; K. K. Purushothaman (1980) Plumbagin: a study of its anticancer, antibacterial and antifungal properties. Indian Journal of Experimental Biology 18: 876-877.
43. Kuete V., S. A. Franco, K. O. Eyong, B. Ngameni, G. N. Folefoc, J. R. Nguemeving, J. G. Tangmouo, G. W. Fotso, J. Komguem, B. M. Ouahouo, J. M. Bolla, J. Chevalier, B. T. Ngadjui, A. E. Nkengfack &; J. M. Pagès (2011) Antibacterial activity of some natural products against bacteria expressing a multidrug-resistant phenotype. International Journal of Antimicrobial agents 37: 156-161.
44. Lee H. H., M. N. Molla, C. R. Cantor &; J. J. Collins (2010) Bacterial charity work leads to population-wide resistance. Nature 467: 82–85.
45. Lee J. H., J. H. Yeon, H. Kim, W. Roh, J. Chae, H. O. Park &; D. M. Kim (2012) The natural anticancer agent plumbagin induces potent cytotoxicity in MCF-7 human breast cancer cells by inhibiting a PI-5 kinase for ROS generation. PLoS One 7: e45023.
46. Li Z. &; B. Demple (1994) SoxS, an activator of superoxide stress genes in Escherichia coli. Purification and interaction with DNA. Journal of Biological Chemistry. 269:18371–18377.
47. Lichstein H. C. &; V. F.Van De Sand (1946) The antibiotic activity of violacein, prodigiosin, and phthiocol. Journal of Bacteriology 52: 145-146.
48. Lin C. N., W. J. Syu, W. S. Sun, J. W. Chen, T. H. Chen, M. J. Don &; S. H.Wang (2010) A role of ygfZ in the Escherichia coli response to plumbagin challenge. Journal of Biomedical Science 17: 84-97.
49. Lomovskaya O. &; A. B. Keith (2006) Practical applications and feasibility of efflux pump inhibitors in the clinic — a vision for applied use. Biochemical Pharmacology 71: 910-918.
50. Magnet S., P. Courvalin &; T. Lambert (2001) Resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM4454. Antimicrobial Agents and Chemotherapy 45: 3375-3380.
51. Martin R. G. &; J. L. Rosner (1995) Binding of purified multiple antibiotic-resistance repressor protein (MarR) to mar operator sequences. Proceedings of the National Academy of Sciences USA. 92:5456–5460.
52. Martin R. G. &; J. L. Rosner (1997) Fis, an accessorial factor for transcriptional activation of the mar (multiple antibiotic resistances) promoter of Escherichia coli in the presence of the activator MarA, SoxS, or Rob. Journal of Bacteriology. 179:7410–7419.
53. Martin R. G. &; J. L. Rosner (2002) Genomics of the marA/soxS/rob regulon of Escherichia coli: identification of directly activated promoters by application of molecular genetics and informatics to microarray data. Molecular Microbiology 44: 1611-1624.
54. Martin R. G. &; J. L. Rosner (2004) Transcriptional and translational regulation of the marRAB multiple antibiotic resistance operon in Escherichia coli. Molecular Microbiology. 53:183–191.
55. Martin R. G., K. W. Jair, R. E. Wolf &; J. L. Rosner (1996) Autoactivation of the marRAB multiple antibiotic resistance operon by the MarA transcriptional activator in Escherichia coli. Journal of Bacteriology. 178:2216–2223.
56. Martin R. G., W. K. Gillette, S. Rhee &; J. L. Rosner (1999) Structural requirements for marbox function in transcriptional activation of mar/sox/rob regulon promoters in Escherichia coli: sequence, orientation and spatial relationship to the core promoter. Molecular Microbiology. 34: 431-441.
57. Martin R. G., W. K. Gillette &; J. L. Rosner (2000) Promoter discrimination by the related transcriptional activators MarA and SoxS: differential regulation by differential binding. Molecular Microbiology. 35:623–634.
58. McMurry L. M. &; Levy S. B. (2010) Evidence that regulatory protein MarA of Escherichia coli represses rob by steric hindrance. Journal of Bacteriology 192:3977–3982.
59. Médigue C., T. Rouxel, P. Vigier, A. Hénaut &; A. Danchin (1991) Evidence for horizontal gene transfer in Escherichia coli speciation. Journal of Molecular Biology 222: 851–856
60. Melican K., R. M. Sandoval, A. Kader, L. Josefsson, G. A. Tanner, B. A. Molitoris &; A. R. Dahlfors (2011) Uropathogenic Escherichia coli P and type 1 fimbriae act in synergy in a living host to facilitate renal colonization leading to nephron obstruction. PLoS Pathogens 7: e1001298.
61. Michan C, M. Manchado &; C. Pueyo (2002) SoxRS down-regulation of rob transcription. Journal of Bacteriology 184:4733–4738.
62. Miller P. F., L. F. Gambino, M. C. Sulavik &; S. J. Gracheck (1994) Genetic relationship between soxRS and mar loci in promoting multiple antibiotic resistance in Escherichia coli. Antimicrobial Agents and Chemotherapy 38:1773–1779.
63. Minotti G., P. Menna, E. Salvatorelli, G. Cairo &; L.Gianni (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological Reviews 56: 185-229.
64. Mohsen A., M. E. Omar &; N. S. Habib (1987) Some novel phthiocol and menadione thiosemicarbozone derivatives as potential anticancer and antimicrobial agents. Pharmazie. 33:81-82.
65. Moore D. S., G. P. McCabe &; B. A. Craig. Introduction to the Practice of Statistics. W.H. Freeman &; Company, 7th edition, 2011. ISBN: 9781429286640
66. Nakao H. &; T. Takeda (2000) Escherichia coli shiga toxin. Journal of Natural Toxins 9: 299-313.
67. Nikaido H. (2009) Multidrug resistance in bacteria. Annual Review of Biochemistry 78: 119–46.
68. Nishino K., J. Yamada, H. Hirakawa, T. Hirata &; A. Yamaguchi (2003) Roles of TolC-dependent multidrug transporters of Escherichia coli in resistance to β-lactams. Antimicrobial Agents and Chemotherapy 47: 3030-3033.
69. Nunoshiba T., E. Hidalgo, C. F. Amabile Cuevas &; B. Demple (1992) Two-stage control of an oxidative stress regulon: the Escherichia coli SoxR protein triggers redox-inducible expression of the soxS regulatory gene. Journal of Bacteriology 174:6054–6060.
70. Ote T., M. Hashimoto, Y. Ikeuchi, M. Su'etsugu, T. Suzuki, T. Katayama &; J. Kato (2006) Involvement of the Escherichia coli folate-binding protein YgfZ in RNA modification and regulation of chromosomal replication initiation. Journal of Molecular Biology 59: 265-275.
71. Park B.S., H. K. Lee, S. E. Lee, X. L. Piao, G. R. Takeoka, R. Y. Wong, Y. J. Ahn &; J. H. Kim (2006) Antibacterial activity of Tabebuia impetiginosa Martius ex DC (Taheebo) against Helicobacter pylori. Journal of Ethnopharmacology 105: 255-262.
72. Piddock L. J. V. (2006) Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clinical Microbiology Reviews 19: 382-402
73. Pomposiello P. J., M. H. Bennik &; B. Demple (2001) Genome-wide transcriptional profiling of the Escherichia coli responses to superoxide stress and sodium salicylate. Journal of Bacteriology 183:3890–3902.
74. Prieto-Alamo M. J., N. Abril &; C. Pueyo (1993) Mutagenesis in Escherichia coli K-12 mutants defective in superoxide dismutase or catalase. Oxford Journal 12: 237-244.
75. Rosenberg E. Y., D. Bertenthal, M. L. Nilles, K. P. Bertrand &; H. Nikaido (2003) Bile salts and fatty acids induce the expression of Escherichia coli AcrAB multidrug efflux pump through their interaction with Rob regulatory protein. Molecular Microbiology 48:1609–1619.
76. Rosner J. L., B. Dangi, A. M. Gronenborn &; R. G. Martin (2002) Posttranscriptional activation of the transcriptional activator Rob by dipyridyl in Escherichia coli. Journal of Bacteriology 184:1407–1416.
77. Sauriasari R., D. H. Wang, Y. Takemura, K. Tsutsui, N. Masuoka, K. Sano, M. Horita, B. L. Wang &; K. Ogino (2007). Cytotoxicity of lawsone and cytoprotective activity of antioxidants in catalase mutant Escherichia coli. Toxicology 15: 95-103.
78. Schneiders T. &; S. B. Levy (2006) MarA-mediated transcriptional repression of the rob promoter. Journal of Biological Chemistry 281:10049–10055.
79. Seeger M. A., A. Schiefner, T. Eicher, F. Verrey, K. Diederichs &; K. M. Pos (2006) Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 313: 1295-1298.
80. Seoane A. S. &; S. B. Levy (1995) Characterization of MarR, the repressor of the multiple antibiotic resistance (mar) operon in Escherichia coli. Journal of Bacteriology 177:3414–3419.
81. Shyu J. B., D. P. Lies &; D. K. Newman (2002) Protective role of tolC in efflux of the electron shuttle anthraquinone-2,6-disulfonate. Journal of Bacteriology 184: 1806-1810.
82. Stenflo J., P. Fernlund, W. Egan &; P. Roepstorff (1974) Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proceedings of the National Acdemy of Science USA 71: 2730-2733.
83. Tan T. C. D., H. Osman, S. Mohamad &; A. H. Kamaruddin (2012) Synthesis and antibacterial activity of juglone derivatives. Journal of Chemistry and Chemical Engineering 6: 84-89.
84. Teplyakov A., G. Obmolova, E. Sarikaya, S. Pullalarevu, W. Krajewski, A. Galkin, A. J. Howard, O. Herzberg &; G. L, Gilliland (2004) Crystal structure of the YgfZ protein from Escherichia coli suggests a folate-dependent regulatory role in one-carbon metabolism. Journal of Bacteriology 186: 7134-7140.
85. Thanassi D. G., L. W. Cheng, &; H. Nikaido (1997) Active efflux of bile salts by Escherichia coli. Journal of Bacteriology 179:2512-2518.
86. Tsai C. C., S. Y. Chen &; H. Y. Tsen. (2003) Screening the enteroaggregative Escherichia coli activity and detection of the aggA, aafA, and astA genes with novel PCR primers for the Escherichia coli isolates from diarrhea cases in Taiwan. Diagnostic Microbiology and Infectious Disease46: 159-165.
87. Visalli M. A., E. Murphy, S. J. Projan &; P. A. Bradford (2003) AcrAB multidrug efflux pump is associated with resuced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis. Antimicrobial Agents and Chemotherapy 47: 665-669.
88. Waller J. C., K. W. Ellens, G. Hasnain, S. Alvarez, J. R. Rocca &; A. D.Hanson (2012) Evidence that the folate-dependent proteins YgfZ and MnmEG have opposing effects on growth and on activity of the iron-sulfur enzyme MiaB. Journal of Bacteriology 194: 362-367.
89. Warner D. M. &; S. B. Levy (2010) Different effects of transcriptional regulators MarA, SoxS and Rob on susceptibility of Escherichia coli to cationic antimicrobial peptides (CAMPs): Rob-dependent CAMP induction of the marRAB operon. Microbiology 156:570–578.
90. Webber M. A. &; L. J. Piddock (2003) The importance of efflux pumps in bacterial antibiotic resistance. Journal of Antimicrobial Chemotherapy 51:9-11.
91. WHO. New frontiers in the development of vaccines against enterotoxinogenic (ETEC) and enterohaemorrhagic (EHEC) E. coli infections. Part I. (1999) The Weekly Epidemiological Record 74: 98-101.
92. Wood T. I., K. L. Griffith, W. P. Fawcett, K. W. Jair, T. D. Schneider &; R. E.Wolf (1999) Interdependence of the position and orientation of SoxS binding sites in the transcriptional activation of the class I subset of Escherichia coli superoxide-inducible promoters. Molecular Microbiology 34:414–430.
93. Worthington R.J. &; C.Melander (2013) Combination approaches to combat multidrug-resistant bacteria. Trends in Biotechnology 31:177-84.
94. Wu J. &; B.Weiss (1992) Two-stage induction of the soxRS (superoxide response) regulon of Escherichia coli. Journal of Bacteriology 174:3915–3920.
95. Xu H. L., X. F. Yu, S. C. Qu, X. R. Qu, Y. F. Jiang &; Y. Sui da (2012) Juglone, from Juglans mandshruica Maxim, inhibits growth and induces apoptosis in human leukemia cell HL-60 through a reactive oxygen species-dependent mechanism. Food Chemical Toxicology 50: 590-596.
96. Xu T. P., H. Shen, L. X. Liu &; Y. Q. Shu (2013) Plumbagin from Plumbago zeylanica L induces apoptosis in human non-small cell lung cancer cell lines through NF- κB inactivation. Asian Pacific Journal of Cancer Prevention 14: 2325-2331.
97. Yonatan H. G., P. Godfrey, G. C. Cerquiera, P. M. Kurkdjian, M. Gouali, E. Bingen, T. P. Shea, B. J. Haas, A. Griggs, S. Young, Q. Zeng, M. Lipsitch, M. K. Waldor, F. X. Weill, J. R. Wortman &; W. P. Hanage . (2013) Comparative genomics of recent shiga toxin-producing Escherichia coli O104:H4: short-term evolution of an emerging pathogen. American Society for Microbiology 4: 412-452.