應用大腸桿菌與酵母菌蛋白質體晶片系統性分析抗菌肽及抗生素作用之目標蛋白質

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姓名	巴拉莫(PRAMOD SHAH) 查詢紙本館藏	畢業系所	系統生物與生物資訊研究所
論文名稱	應用大腸桿菌與酵母菌蛋白質體晶片系統性分析抗菌肽及抗生素作用之目標蛋白質 (Systematically analyzing the protein targets of antimicrobial peptides and antibiotics by using Escherichia coli and Saccharomyces cerevisiae proteome microarrays)
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摘要(中)	抗藥性病原菌的增加淡化了抗生素的使用潛力，因此，替代性療法的發展刻不容緩。抗菌肽是先天性免疫系統重要的分子並存在於所有生物體中，近期因其抗菌活性而受到矚目，且有成為抗生素替代品的潛力。抗菌肽有著多元的效用，包括對於病原菌的選擇性、低毒性、低抗藥性和多靶向作用機制。儘管已知其影響細胞膜和細胞內分子多靶點的活性，但目前僅少數靶點被解析出來。在此研究中，高通量蛋白質體微列陣平台被用於系統性分析並廣泛地鑑定抗菌肽的蛋白質靶點，透過平行分析大腸桿菌與酵母菌蛋白質體中所受影響的生物模式。將具有抗細菌和抗真菌活性的抗菌肽，分別使用大腸桿菌蛋白質體和酵母菌蛋白質體微列陣辨識其靶點的蛋白質。其中抗菌肽（Polyphemusin-I、Sub-5、Penetratin、Histatin-5和TWF）將各別應用大腸桿菌蛋白質體微列陣做系統性地辨識其細菌的標靶蛋白質。其中分別找出109個Polyphemusin-I、92個Sub-5、118個Penetratin、93個Histatin-5和48個TWF標靶蛋白質。此外抗菌肽（Lfcin B、Sub-5、Penetratin 和Histatin-5）將各別應用酵母菌蛋白質體微列陣做系統性地辨識其真菌的標靶蛋白質。其中分別找出140個Lfcin B、137個Sub-5、128個Penetratin和123個Histatin-5標靶蛋白質。而這些被抗菌肽（Polyphemusin-I、Sub-5、Penetratin、Histatin-5和TWF）所辨識的細菌標靶蛋白質，透過生物資訊合併分析以了解其抗細菌的活性。同樣地；抗菌肽（Lfcin B、Sub-5、Penetratin 和Histatin-5）所辨識的真菌標靶蛋白質，也透過生物資訊合併分析以了解其抗真菌的活性。在上述實驗中，使用生物素-鏈親和素檢測系統作為訊號檢測的方式，透過標記Dylight（螢光物質）的鏈親和素，辨識生物素化抗菌肽所結合到蛋白質體微列陣上的標靶蛋白質。此外將標記Dylight的鏈親和素直接在蛋白質體微列陣上探測並作為陰性對照組。有趣的是當標記Dylight的鏈親和素直接在大腸桿菌蛋白質體以及酵母菌蛋白質體微列陣上探測時，分別辨識出大腸桿菌與酵母菌生物素化的蛋白質。到目前為止在大腸桿菌與酵母菌分別僅有一種與六種生物素化蛋白質被鑑定出來，而單一生物素修飾蛋白質在生物體的重要性並不清楚。因此透過標記DyLight的鏈親和素在大腸桿菌蛋白質體和酵母菌蛋白質體微陣列上探測，分別鑑定出12種生物素化大腸桿菌蛋白質和44種酵母菌生物素化蛋白質。在鏈親和素的44個標靶蛋白質中，共有30個標靶蛋白可透過標記Dylight抗生物素抗體在酵母菌蛋白質體微列陣中共同被辨識到，這也證明多種生物素化蛋白質存在於酵母菌當中。關於生物肽的靶點以及臨床使用的抗生素靶點也是所知之甚少，而在此研究中也使用一種新穎的方法，分別應用大腸桿菌蛋白質體和酵母菌蛋白質體微陣列來全面性的辨識抗生素的蛋白質靶標。在大腸桿菌蛋白體微列陣辨識已商業化的抗生素靶點，其中鑑定出93個Sulfamethoxazole、81個Trimethoprim、87個 Minocycline、65個 Streptomycin和88個Vancomycin的蛋白質靶點。將這些被鑑定出的抗生素蛋白質靶點進行生物資訊分析一併了解其抗菌活性。而酵母菌蛋白質體微列陣解析出Sulfamethoxazole總共有33個真菌蛋白質靶點。透過生物資訊學探究Sulfamethoxazole的抗真菌活性，也同時比較其抗菌和抗真菌靶點。此外從大腸桿菌蛋白質體和酵母菌蛋白質體微列陣所發現的抗菌肽標靶蛋白質，進一步探究其抗細菌和抗真菌病原體活性的機制差異，比較的結果指出相同抗菌肽或抗生素在細菌與真菌中所採用的機制完全不同。此外透過蛋白質體微列陣的分析方法，鑑定抗菌肽和抗生素的蛋白質靶點不僅提供了對抗菌肽和抗生素機制的理解，也被證明可作為探討組合協同作用機制的工具。相較於單獨使用的抑制效果總和，合併治療中觀察到更顯著優異的抑制效果被稱為組合協同作用。組合協同作用具有多種優點，如增強抗生素治療的潛力，減少單一抗生素使用的劑量從而降低其毒性、延長抗藥性的產生以及對於抗藥性病原體產生的強勁影響。關於抗生素靶點的知識有限，以至於組合協同作用的機制尚不清楚。因此鑑定抗菌肽和抗生素的整體蛋白質靶點，將更清楚地解釋組合協同作用的機制。在相同途徑中的共同富集導致在抗菌肽-抗菌肽，抗菌肽-抗生素以及抗生素-抗生素之間發現新的協同組合預測。另外合成致死方法用於研究抗菌肽真菌蛋白質靶點之間的合成致死組合。基於已發現的合成致死組合及其參與相同的蛋白質複合物和可逆功能，預測了Lfcin B和Histatin-5的組合協同作用，並且在體內實驗中透過單獨使用或組合的Lfcin B和Histatin-5，驗證了其對酵母菌的生長抑制曲線。
摘要(英)	Abstract Increase in resistance pathogens have fade the potential of antibiotics. Thus, alternatives therapies are investigated to conquer the battle of resistance. Antimicrobial peptides (AMPs), the key molecules of innate immunity, are present in all organism and recently gaining attention for its antimicrobial activities as well as antibiotics’ alternative. AMPs exert wide range of activity, have selective nature for pathogenic, lower toxicity, minimal resistance development properties and multiple-targeting mechanism of actions. Despite the knowledge of its multi-targeting activities on cellular membrane and intracellular molecules, only few targets have been identified. In this study, the high-throughput platform of proteome microarrays was utilized for systematical and comprehensive identification of the entire protein targets of AMPs in parallel analysis to the entire proteome of the model organisms: Escherichia coli and Saccharomyces cerevisiae. Intracellular targeting AMPs with antibacterial and antifungal activities were probed on Escherichia coli proteome microarrays and Saccharomyces cerevisiae proteome microarrays to identify their antibacterial and antifungal protein targets, respectively. The bacterial protein targets of AMPs with antibacterial activities (Polyphemusin-I, Sub-5, Penetratin, Histatin-5 and TWF) were systematically identified by individually probing the AMPs on Escherichia coli proteome microarrays. In total of 109, 92, 118, 93 and 48 protein targets were identified for Polyphemusin-I, Sub-5, Penetratin, Histatin-5 and TWF, respectively. The fungal protein targets of AMPs with antifungal activities (Lfcin B, Sub-5, Penetratin and Histatin-5) were systematically identified by individually probing the AMPs on Saccharomyces cerevisiae proteome microarrays. In total of 140, 137, 128 and 123 protein targets were identified for Lfcin B, Sub-5, Penetratin and Histatin-5,respectively. These identified bacterial protein targets of AMPs (Polyphemusin-I, Sub-5, Penetratin, Histatin-5 and TWF) were bioinformatically analyzed together to understand their antibacterial activities. Also, the identified fungal protein targets of AMPs (Lfcin B, Sub-5, Penetratin and Histatin-5) were bioinformatically analyzed together to understand their antifungal activities. In above assays, biotin-streptavidin detection system was used for the signal detection of the biotinylated AMPs bound to the protein targets on proteome microarrays with streptavidin labeled DyLight (fluorescence). As a negative control, only streptavidin labeled DyLight was probing on proteome microarrays. Interesting by probing only streptavidin labeled DyLight on the Escherichia coli proteome microarrays as well as Saccharomyces cerevisiae proteome microarrays, the biotinylated proteins (proteins modification by biotin) of the Escherichia coli and Saccharomyces cerevisiae were identified, respectively. So far, only one biotinylated protein has been identified in Escherichia coli and six biotinylated proteins in Saccharomyces cerevisiae. The essentiality of biotin in living organism cannot be understood by single biotin modified protein. Thus, by probing streptavidin label DyLight on Escherichia coli proteome microarrays and Saccharomyces cerevisiae proteome microarrays, in total of 12 biotinylated proteins for Escherichia coli and 44 biotinylated proteins for Saccharomyces cerevisiae were identified, respectively. Among 44 protein targets of Streptavidin, 30 protein targets overlapped with the protein targets of Anti-biotin labeled Dylight on Saccharomyces cerevisiae proteome microarrays. This anti-biotin probing confirmed the presence of several biotinylated proteins in Saccharomyces cerevisiae. In regard to the targets of AMPs, the entire targets of clinically used antibiotics are also poorly understood. Thus, a novel approach was also used in this study to identify the entire protein targets of antibiotics by utilizing Escherichia coli proteome microarrays and Saccharomyces cerevisiae proteome microarrays, respectively. In total of 93, 81, 87, 65 and 88 protein targets of Sulfamethoxazole, Trimethoprim, Minocycline, Streptomycin and Vancomycin, the commercial antibiotics, were identified from Escherichia coli proteome microarrays. These identified protein targets of antibiotics were bioinformatically analyzed together to understand their antibacterial activities. Whereas, the fungal protein targets of Sulfamethoxazole obtained from Saccharomyces cerevisiae proteome microarrays probing was 33 protein targets in total. Bioinformatics were performed to explore the antifungal activities of Sulfamethoxazole as well as compared the antibacterial and antifungal targets of Sulfamethoxazole. Moreover, the identified protein targets of AMPs from Escherichia coli proteome microarrays as well as Saccharomyces cerevisiae proteome microarrays were further compared to identify the mechanistic difference in their activities against bacterial and fungal pathogens. The comparison results showed completely different mechanism of action of same AMPs and antibiotic in case of bacteria and fungi. Furthermore, the identified protein targets of AMPs and antibiotics from the proteome microarrays approach not only provided the understanding for the mechanism of AMPs and antibiotics but also proved to be a useful tool to study the mechanism of synergistic combinations. The significant higher inhibition effect observed in combination than the sum of individual inhibition is termed as synergistic combination. Synergistic combination has multiple advantages, like enhancing the potential of antibiotics, reducing the doses of individual antibiotics thus lowering their toxicity, prolong in the resistance development as well as exert powerful effect on resistance pathogens. In regard to the limited knowledge of antibiotic target, the mechanism of synergistic combination is unclear. Hence, the entire protein targets identified for AMPs and antibiotics will more clearly explain the mechanism of synergistic combination. The common enrichment in same pathways resulted in the prediction of new synergistic combinations were discovered between AMP and AMP, AMP and antibiotic as well as antibiotic and antibiotic. As well as synthetic lethality approach was used to identify the synthetic lethal pairs between the identified fungal protein targets of AMPs. Based on identified synthetic lethal pairs and their involvement in same protein complex and reversible functions, the synergistic combination was predicted between Lfcin B and Histatin-5 and was experimentally validate in vivo by inhibition growth curve of Saccharomyces cerevisiae in the presence of individual and combination of Lfcin B and Histatin-5.
關鍵字(中)	★ 蛋白質組微陣列 ★ 抗菌肽 ★ 抗生素 ★ 大腸桿菌 ★ 酵母菌 ★ 手術	關鍵字(英)	★ Proteome microarray ★ Antimicrobial peptides (AMPs) ★ Antibiotics ★ Escherichia coli ★ Saccharomyces cerevisiae ★ synergy
論文目次	Table of contents 摘要 (Chinese Abstract) ...................................................................................................... I Abstract ............................................................................................................................. IV Chapter 1 : Proteome microarrays and the overview of this study ..................................... 1 Abstract ........................................................................................................................... 1 Introduction ..................................................................................................................... 2 Proteome microarrays ..................................................................................................... 3 Proteome microarrays and its application on target identification .................................. 6 AIM of this study ............................................................................................................ 7 Chapter 2 : Literature review on Antimicrobial peptides ................................................. 10 Abstract ......................................................................................................................... 10 Introduction ................................................................................................................... 11 Antimicrobial peptides (AMPs)................................................................................. 11 History of AMPs ........................................................................................................ 11 Origin and characteristic of AMPs ............................................................................ 12 AMPs and their biological significance ..................................................................... 15 Structural classification of AMPs .............................................................................. 16 Common properties of AMPs .................................................................................... 17 Mechanism of action of AMPs .................................................................................. 19 Membrane lytic mechanism....................................................................................... 21 XI Cell membrane (lipid bilayer) targeting AMPs ..................................................... 21 Cell wall targeting AMPs....................................................................................... 23 Lipid II (cell wall precursor) targeting AMPs ....................................................... 23 Capsule (or polysaccharide layer) targeting AMPs ............................................... 25 Lipopolysaccharide (LPS) targeting AMPs ........................................................... 25 Transportation of AMPs across cell membrane ........................................................ 26 Non-membrane lytic mechanism ............................................................................... 27 DNA/ RNA targeting AMPs .................................................................................. 28 Protein targeting AMPs.......................................................................................... 30 AMPs targeting protein folding chaperones .......................................................... 30 AMPS targeting enzymes ...................................................................................... 31 Cell-division targeting AMPs ................................................................................ 31 Proteome microarrays and its application for target identification of AMPs ............ 33 Lactoferricin B ....................................................................................................... 35 Bactenecin 7 ........................................................................................................... 36 Proline-arginine rice peptide with 39 residues....................................................... 37 Hybrid of pleurocidin and dermaseptin ................................................................. 38 Discussion ..................................................................................................................... 39 Chapter 3 : Systematical identification and analysis of protein targets of intracellular targeting antimicrobial peptides by using Escherichia coli proteome microarrays ....................................................................................................................... 41 Abstract ......................................................................................................................... 41 Keywords: ..................................................................................................................... 42 Introduction ................................................................................................................... 43 RESULTS...................................................................................................................... 49 Discussion ..................................................................................................................... 73 Chapter 4 : Probing of streptavidin on proteome microarrays – as a negative control and the identified targets are the naturally biotinylated proteins .......................... 75 Abstract ......................................................................................................................... 75 Keywords: ..................................................................................................................... 76 RESULTS...................................................................................................................... 83 Discussion ................................................................................................................... 105 Chapter 5 : Systematical identification and analysis of protein targets of commercially available antibiotics by using Escherichia coli proteome microarrays ... 108 Abstract ....................................................................................................................... 108 Keywords: ................................................................................................................... 109 RESULTS.................................................................................................................... 115 Discussion ................................................................................................................... 133 Chapter 6 : Systemically discovering the new synergistic combinations as well as deciphering the synergistic mechanism of known antimicrobial peptides and antibiotics by using Escherichia coli proteome microarray ........................................... 134 Abstract ....................................................................................................................... 134 Introduction ................................................................................................................. 136 RESULTS.................................................................................................................... 141 Discussion ................................................................................................................... 146 Chapter 7 : Systematical identification and analysis of protein targets of antimicrobial peptides with antifungal activity using Saccharomyces cerevisiae proteome microarrays ..................................................................................................... 150 Abstract ....................................................................................................................... 150 Keywords: ................................................................................................................... 151 Introduction ................................................................................................................. 152 Results ......................................................................................................................... 157 Discussion ................................................................................................................... 184 Chapter 8 : Systematical identification and analysis of protein targets of antibiotics reported with antifungal activities by using Saccharomyces cerevisiae proteome microarrays ..................................................................................................................... 187 Abstract ....................................................................................................................... 187 Keywords: ................................................................................................................... 188 Introduction ................................................................................................................. 188 RESULTS.................................................................................................................... 191 Discussion ................................................................................................................... 202 Chapter 9 : Systemically discovering the synergistic combinations between antimicrobial peptides with antifungal activity from the identified protein targets using Saccharomyces cerevisiae proteome microarrays ................................................. 204 Abstract ....................................................................................................................... 204 Keywords: ................................................................................................................... 205 Introduction ................................................................................................................. 206 RESULTS.................................................................................................................... 209 Discussion ................................................................................................................... 225 Chapter 10 : Deciphering the antibacterial and antifungal mechanism of antimicrobial peptides from their identified protein targets by using Escherichia coli proteome microarrays and Saccharomyces cerevisiae proteome microarrays ............... 227 Abstract ....................................................................................................................... 227 Introduction ................................................................................................................. 228 RESULTS.................................................................................................................... 229 Discussion ................................................................................................................... 242 Chapter 11 : Materials and Methods ............................................................................... 243 Chapter 12 : References .................................................................................................. 272
參考文獻	1. Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol. 1992;119(2):301-11. 2. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993;333(1-2):169-74. 3. Wangler MF, Yamamoto S, Chao HT, Posey JE, Westerfield M, Postlethwait J, et al. Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research. Genetics. 2017;207(1):9-27. 4. Zhu H, Bilgin M, Bangham R, Hall D, Casamayor A, Bertone P, et al. Global analysis of protein activities using proteome chips. Science. 2001;293(5537):2101-5. 5. Chen CS, Korobkova E, Chen H, Zhu J, Jian X, Tao SC, et al. A proteome chip approach reveals new DNA damage recognition activities in Escherichia coli. Nature methods. 2008;5(1):69-74. 6. Garcia-Valiente R, Fernandez-Garcia J, Carabias-Sanchez J, Landeira-Vinuela A, Gongora R, Gonzalez-Gonzalez M, et al. A Systematic Analysis Workflow for High-Density Customized Protein Microarrays in Biomarker Screening. Methods Mol Biol. 2019;1871:107-22. 7. Sutandy FX, Qian J, Chen CS, Zhu H. Overview of protein microarrays. Curr Protoc Protein Sci. 2013;Chapter 27:Unit 27 1. 8. Chen CS, Zhu H. Protein microarrays. Biotechniques. 2006;40(4):423, 5, 7 passim. 273 9. Lueking A, Possling A, Huber O, Beveridge A, Horn M, Eickhoff H, et al. A nonredundant human protein chip for antibody screening and serum profiling. Mol Cell Proteomics. 2003;2(12):1342-9. 10. Chandra H, Reddy PJ, Srivastava S. Protein microarrays and novel detection platforms. Expert review of proteomics. 2011;8(1):61-79. 11. Zhu H, Qian J. Applications of functional protein microarrays in basic and clinical research. Adv Genet. 2012;79:123-55. 12. Toke O. Antimicrobial peptides: new candidates in the fight against bacterial infections. Biopolymers. 2005;80(6):717-35. 13. Hancock RE, Patrzykat A. Clinical development of cationic antimicrobial peptides: from natural to novel antibiotics. Curr Drug Targets Infect Disord. 2002;2(1):79-83. 14. Fleming A. On a Remarkable Bacteriolytic Element Found in Tissues and Secretions. Proceedings of the Royal Society of London Series B, Containing Papers of a Biological Character. 1922;93(653):306-17. 15. Canfield RE. The Amino Acid Sequence of Egg White Lysozyme. J Biol Chem. 1963;238:2698-707. 16. Dubos RJ. Studies on a Bactericidal Agent Extracted from a Soil Bacillus : I. Preparation of the Agent. Its Activity in Vitro. J Exp Med. 1939;70(1):1-10. 17. Dubos RJ. Studies on a Bactericidal Agent Extracted from a Soil Bacillus : Ii. Protective Effect of the Bactericidal Agent against Experimental Pneumococcus Infections in Mice. J Exp Med. 1939;70(1):11-7. 18. Bahar AA, Ren D. Antimicrobial peptides. Pharmaceuticals (Basel). 2013;6(12):1543-75. 274 19. Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA, et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature. 2001;414(6862):454-7. 20. Scott MG, Rosenberger CM, Gold MR, Finlay BB, Hancock RE. An alpha-helical cationic antimicrobial peptide selectively modulates macrophage responses to lipopolysaccharide and directly alters macrophage gene expression. J Immunol. 2000;165(6):3358-65. 21. Bals R. Epithelial antimicrobial peptides in host defense against infection. Respir Res. 2000;1(3):141-50. 22. Mansour SC, Pena OM, Hancock RE. Host defense peptides: front-line immunomodulators. Trends Immunol. 2014;35(9):443-50. 23. Sorensen OE, Borregaard N, Cole AM. Antimicrobial peptides in innate immune responses. Contrib Microbiol. 2008;15:61-77. 24. Ganz T. The role of antimicrobial peptides in innate immunity. Integr Comp Biol. 2003;43(2):300-4. 25. Porto WF, Nolasco DO, Pires AS, Pereira RW, Franco OL, Alencar SA. Prediction of the impact of coding missense and nonsense single nucleotide polymorphisms on HD5 and HBD1 antibacterial activity against Escherichia coli. Biopolymers. 2016;106(5):633-44. 26. Park SC, Park Y, Hahm KS. The role of antimicrobial peptides in preventing multidrug-resistant bacterial infections and biofilm formation. Int J Mol Sci. 2011;12(9):5971-92. 275 27. Yeaman MR, Yount NY. Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev. 2003;55(1):27-55. 28. Singh PK, Parsek MR, Greenberg EP, Welsh MJ. A component of innate immunity prevents bacterial biofilm development. Nature. 2002;417(6888):552-5. 29. Overhage J, Campisano A, Bains M, Torfs EC, Rehm BH, Hancock RE. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infection and immunity. 2008;76(9):4176-82. 30. Ulm H, Wilmes M, Shai Y, Sahl HG. Antimicrobial host defensins - specific antibiotic activities and innate defense modulation. Front Immunol. 2012;3:249. 31. Zhang LJ, Gallo RL. Antimicrobial peptides. Curr Biol. 2016;26(1):R14-9. 32. Hilchie AL, Wuerth K, Hancock RE. Immune modulation by multifaceted cationic host defense (antimicrobial) peptides. Nat Chem Biol. 2013;9(12):761-8. 33. Jenssen H, Hamill P, Hancock RE. Peptide antimicrobial agents. Clin Microbiol Rev. 2006;19(3):491-511. 34. Yang D, Biragyn A, Hoover DM, Lubkowski J, Oppenheim JJ. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu Rev Immunol. 2004;22:181-215. 35. Kumar P, Kizhakkedathu JN, Straus SK. Antimicrobial Peptides: Diversity, Mechanism of Action and Strategies to Improve the Activity and Biocompatibility In Vivo. Biomolecules. 2018;8(1). 36. Hancock RE, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature biotechnology. 2006;24(12):1551-7. 276 37. Lopez Cascales JJ, Zenak S, Garcia de la Torre J, Lezama OG, Garro A, Enriz RD. Small Cationic Peptides: Influence of Charge on Their Antimicrobial Activity. ACS Omega. 2018;3(5):5390-8. 38. Jiang Z, Vasil AI, Hale JD, Hancock RE, Vasil ML, Hodges RS. Effects of net charge and the number of positively charged residues on the biological activity of amphipathic alpha-helical cationic antimicrobial peptides. Biopolymers. 2008;90(3):369-83. 39. Hong SY, Park TG, Lee KH. The effect of charge increase on the specificity and activity of a short antimicrobial peptide. Peptides. 2001;22(10):1669-74. 40. Dathe M, Nikolenko H, Meyer J, Beyermann M, Bienert M. Optimization of the antimicrobial activity of magainin peptides by modification of charge. FEBS Lett. 2001;501(2-3):146-50. 41. Yin LM, Edwards MA, Li J, Yip CM, Deber CM. Roles of hydrophobicity and charge distribution of cationic antimicrobial peptides in peptide-membrane interactions. J Biol Chem. 2012;287(10):7738-45. 42. Chen Y, Guarnieri MT, Vasil AI, Vasil ML, Mant CT, Hodges RS. Role of peptide hydrophobicity in the mechanism of action of alpha-helical antimicrobial peptides. Antimicrob Agents Chemother. 2007;51(4):1398-406. 43. Takahashi D, Shukla SK, Prakash O, Zhang G. Structural determinants of host defense peptides for antimicrobial activity and target cell selectivity. Biochimie. 2010;92(9):1236-41. 44. Mihajlovic M, Lazaridis T. Charge distribution and imperfect amphipathicity affect pore formation by antimicrobial peptides. Biochim Biophys Acta. 2012;1818(5):1274-83. 277 45. Chen Y, Mant CT, Farmer SW, Hancock RE, Vasil ML, Hodges RS. Rational design of alpha-helical antimicrobial peptides with enhanced activities and specificity/therapeutic index. J Biol Chem. 2005;280(13):12316-29. 46. Zhang SK, Song JW, Gong F, Li SB, Chang HY, Xie HM, et al. Design of an alpha-helical antimicrobial peptide with improved cell-selective and potent anti-biofilm activity. Sci Rep. 2016;6:27394. 47. Edwards IA, Elliott AG, Kavanagh AM, Zuegg J, Blaskovich MA, Cooper MA. Contribution of Amphipathicity and Hydrophobicity to the Antimicrobial Activity and Cytotoxicity of beta-Hairpin Peptides. ACS Infect Dis. 2016;2(6):442-50. 48. Smirnova MP, Afonin VG, Shpen VM, Tiagotin Iu V, Kolodkin NI. [Structure-function relationship between analogues of the antibacterial peptide indolicidin. I. Synthesis and biological activity of analogues with increased amphipathicity and elevated net positive charge of the molecule]. Bioorg Khim. 2004;30(5):458-65. 49. Wimley WC, Hristova K. Antimicrobial peptides: successes, challenges and unanswered questions. J Membr Biol. 2011;239(1-2):27-34. 50. Shah P, Hsiao FS, Ho YH, Chen CS. The proteome targets of intracellular targeting antimicrobial peptides. Proteomics. 2016;16(8):1225-37. 51. Le CF, Fang CM, Sekaran SD. Intracellular Targeting Mechanisms by Antimicrobial Peptides. Antimicrob Agents Chemother. 2017;61(4). 52. Cudic M, Otvos L, Jr. Intracellular targets of antibacterial peptides. Curr Drug Targets. 2002;3(2):101-6. 53. Casteels P, Ampe C, Jacobs F, Vaeck M, Tempst P. Apidaecins: antibacterial peptides from honeybees. EMBO J. 1989;8(8):2387-91. 278 54. Shai Y. Mode of action of membrane active antimicrobial peptides. Biopolymers. 2002;66(4):236-48. 55. Matsuzaki K, Sugishita K, Harada M, Fujii N, Miyajima K. Interactions of an antimicrobial peptide, magainin 2, with outer and inner membranes of Gram-negative bacteria. Biochim Biophys Acta. 1997;1327(1):119-30. 56. Matsuzaki K. Control of cell selectivity of antimicrobial peptides. Biochim Biophys Acta. 2009;1788(8):1687-92. 57. Lohner K, Prenner EJ. Differential scanning calorimetry and X-ray diffraction studies of the specificity of the interaction of antimicrobial peptides with membrane-mimetic systems. Biochim Biophys Acta. 1999;1462(1-2):141-56. 58. Brotz H, Bierbaum G, Leopold K, Reynolds PE, Sahl HG. The lantibiotic mersacidin inhibits peptidoglycan synthesis by targeting lipid II. Antimicrob Agents Chemother. 1998;42(1):154-60. 59. de Kruijff B, van Dam V, Breukink E. Lipid II: a central component in bacterial cell wall synthesis and a target for antibiotics. Prostaglandins Leukot Essent Fatty Acids. 2008;79(3-5):117-21. 60. Breukink E, de Kruijff B. Lipid II as a target for antibiotics. Nat Rev Drug Discov. 2006;5(4):321-32. 61. Henrichfreise B, Schiefer A, Schneider T, Nzukou E, Poellinger C, Hoffmann TJ, et al. Functional conservation of the lipid II biosynthesis pathway in the cell wall-less bacteria Chlamydia and Wolbachia: why is lipid II needed? Mol Microbiol. 2009;73(5):913-23. 279 62. Campos MA, Vargas MA, Regueiro V, Llompart CM, Alberti S, Bengoechea JA. Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides. Infect Immun. 2004;72(12):7107-14. 63. Le CF, Gudimella R, Razali R, Manikam R, Sekaran SD. Transcriptome analysis of Streptococcus pneumoniae treated with the designed antimicrobial peptides, DM3. Sci Rep. 2016;6:26828. 64. Yethon JA, Whitfield C. Lipopolysaccharide as a target for the development of novel therapeutics in gram-negative bacteria. Curr Drug Targets Infect Disord. 2001;1(2):91-106. 65. Gough M, Hancock RE, Kelly NM. Antiendotoxin activity of cationic peptide antimicrobial agents. Infect Immun. 1996;64(12):4922-7. 66. Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol. 2005;3(3):238-50. 67. Nguyen LT, Haney EF, Vogel HJ. The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol. 2011;29(9):464-72. 68. Hale JD, Hancock RE. Alternative mechanisms of action of cationic antimicrobial peptides on bacteria. Expert Rev Anti Infect Ther. 2007;5(6):951-9. 69. Nissen-Meyer J, Nes IF. Ribosomally synthesized antimicrobial peptides: their function, structure, biogenesis, and mechanism of action. Arch Microbiol. 1997;167(2/3):67-77. 70. Nicolas P. Multifunctional host defense peptides: intracellular-targeting antimicrobial peptides. FEBS J. 2009;276(22):6483-96. 280 71. Lavina M, Pugsley AP, Moreno F. Identification, mapping, cloning and characterization of a gene (sbmA) required for microcin B17 action on Escherichia coli K12. J Gen Microbiol. 1986;132(6):1685-93. 72. Jarver P, Langel U. Cell-penetrating peptides--a brief introduction. Biochim Biophys Acta. 2006;1758(3):260-3. 73. Snyder EL, Dowdy SF. Cell penetrating peptides in drug delivery. Pharm Res. 2004;21(3):389-93. 74. Zorko M, Langel U. Cell-penetrating peptides: mechanism and kinetics of cargo delivery. Adv Drug Deliv Rev. 2005;57(4):529-45. 75. Madani F, Lindberg S, Langel U, Futaki S, Graslund A. Mechanisms of cellular uptake of cell-penetrating peptides. J Biophys. 2011;2011:414729. 76. Hilpert K, Volkmer-Engert R, Walter T, Hancock RE. High-throughput generation of small antibacterial peptides with improved activity. Nat Biotechnol. 2005;23(8):1008-12. 77. Hsu CH, Chen C, Jou ML, Lee AY, Lin YC, Yu YP, et al. Structural and DNA-binding studies on the bovine antimicrobial peptide, indolicidin: evidence for multiple conformations involved in binding to membranes and DNA. Nucleic Acids Res. 2005;33(13):4053-64. 78. Marchand C, Krajewski K, Lee HF, Antony S, Johnson AA, Amin R, et al. Covalent binding of the natural antimicrobial peptide indolicidin to DNA abasic sites. Nucleic Acids Res. 2006;34(18):5157-65. 281 79. Yonezawa A, Kuwahara J, Fujii N, Sugiura Y. Binding of tachyplesin I to DNA revealed by footprinting analysis: significant contribution of secondary structure to DNA binding and implication for biological action. Biochemistry. 1992;31(11):2998-3004. 80. Park CB, Kim HS, Kim SC. Mechanism of action of the antimicrobial peptide buforin II: buforin II kills microorganisms by penetrating the cell membrane and inhibiting cellular functions. Biochem Biophys Res Commun. 1998;244(1):253-7. 81. Sugiarto H, Yu PL. Mechanisms of action of ostrich beta-defensins against Escherichia coli. FEMS Microbiol Lett. 2007;270(2):195-200. 82. Xiong YQ, Yeaman MR, Bayer AS. In vitro antibacterial activities of platelet microbicidal protein and neutrophil defensin against Staphylococcus aureus are influenced by antibiotics differing in mechanism of action. Antimicrob Agents Chemother. 1999;43(5):1111-7. 83. Castle M, Nazarian A, Yi SS, Tempst P. Lethal effects of apidaecin on Escherichia coli involve sequential molecular interactions with diverse targets. J Biol Chem. 1999;274(46):32555-64. 84. Calloni G, Chen T, Schermann SM, Chang HC, Genevaux P, Agostini F, et al. DnaK functions as a central hub in the E. coli chaperone network. Cell Rep. 2012;1(3):251-64. 85. Kumar CM, Mande SC, Mahajan G. Multiple chaperonins in bacteria--novel functions and non-canonical behaviors. Cell Stress Chaperones. 2015;20(4):555-74. 86. Rahnamaeian M, Cytrynska M, Zdybicka-Barabas A, Dobslaff K, Wiesner J, Twyman RM, et al. Insect antimicrobial peptides show potentiating functional interactions against Gram-negative bacteria. Proc Biol Sci. 2015;282(1806):20150293. 282 87. Otvos L, Jr., O I, Rogers ME, Consolvo PJ, Condie BA, Lovas S, et al. Interaction between heat shock proteins and antimicrobial peptides. Biochemistry. 2000;39(46):14150-9. 88. Kragol G, Lovas S, Varadi G, Condie BA, Hoffmann R, Otvos L, Jr. The antibacterial peptide pyrrhocoricin inhibits the ATPase actions of DnaK and prevents chaperone-assisted protein folding. Biochemistry. 2001;40(10):3016-26. 89. Li W-F, Ma G-X, Zhou X-X. Apidaecin-type peptides: Biodiversity, structure–function relationships and mode of action. Peptides. 2006;27(9):2350-9. 90. Parks WM, Bottrill AR, Pierrat OA, Durrant MC, Maxwell A. The action of the bacterial toxin, microcin B17, on DNA gyrase. Biochimie. 2007;89(4):500-7. 91. Heddle JG, Blance SJ, Zamble DB, Hollfelder F, Miller DA, Wentzell LM, et al. The antibiotic microcin B17 is a DNA gyrase poison: characterisation of the mode of inhibition. J Mol Biol. 2001;307(5):1223-34. 92. Mukhopadhyay J, Sineva E, Knight J, Levy RM, Ebright RH. Antibacterial peptide microcin J25 inhibits transcription by binding within and obstructing the RNA polymerase secondary channel. Mol Cell. 2004;14(6):739-51. 93. Fogaca AC, Almeida IC, Eberlin MN, Tanaka AS, Bulet P, Daffre S. Ixodidin, a novel antimicrobial peptide from the hemocytes of the cattle tick Boophilus microplus with inhibitory activity against serine proteinases. Peptides. 2006;27(4):667-74. 94. Couto MA, Harwig SS, Lehrer RI. Selective inhibition of microbial serine proteases by eNAP-2, an antimicrobial peptide from equine neutrophils. Infect Immun. 1993;61(7):2991-4. 283 95. Nishikata M, Kanehira T, Oh H, Tani H, Tazaki M, Kuboki Y. Salivary histatin as an inhibitor of a protease produced by the oral bacterium Bacteroides gingivalis. Biochem Biophys Res Commun. 1991;174(2):625-30. 96. Salomon RA, Farias RN. Microcin 25, a novel antimicrobial peptide produced by Escherichia coli. J Bacteriol. 1992;174(22):7428-35. 97. Ishikawa M, Kubo T, Natori S. Purification and characterization of a diptericin homologue from Sarcophaga peregrina (flesh fly). Biochem J. 1992;287 ( Pt 2):573-8. 98. Chileveru HR, Lim SA, Chairatana P, Wommack AJ, Chiang IL, Nolan EM. Visualizing attack of Escherichia coli by the antimicrobial peptide human defensin 5. Biochemistry. 2015;54(9):1767-77. 99. Tu YH, Ho YH, Chuang YC, Chen PC, Chen CS. Identification of lactoferricin B intracellular targets using an Escherichia coli proteome chip. PLoS One. 2011;6(12):e28197. 100. Ho YH, Sung TC, Chen CS. Lactoferricin B inhibits the phosphorylation of the two-component system response regulators BasR and CreB. Mol Cell Proteomics. 2012;11(4):M111 014720. 101. Ho YH, Shah P, Chen YW, Chen CS. Systematic Analysis of Intracellular-targeting Antimicrobial Peptides, Bactenecin 7, Hybrid of Pleurocidin and Dermaseptin, Proline-Arginine-rich Peptide, and Lactoferricin B, by Using Escherichia coli Proteome Microarrays. Mol Cell Proteomics. 2016;15(6):1837-47. 102. Masson PL, Heremans JF, Dive CH. An iron-binding protein common to many external secretions. Clinica Chimica Acta. 1966;14(6):735-9. 284 103. Kuwata H, Yip TT, Tomita M, Hutchens TW. Direct evidence of the generation in human stomach of an antimicrobial peptide domain (lactoferricin) from ingested lactoferrin. Biochim Biophys Acta. 1998;1429(1):129-41. 104. Longhi C, Conte MP, Bellamy W, Seganti L, Valenti P. Effect of lactoferricin B, a pepsin-generated peptide of bovine lactoferrin, on Escherichia coli HB101 (pRI203) entry into HeLa cells. Medical microbiology and immunology. 1994;183(2):77-85. 105. Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I. Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Japanese journal of cancer research : Gann. 1997;88(2):184-90. 106. Hwang PM, Zhou N, Shan X, Arrowsmith CH, Vogel HJ. Three-dimensional solution structure of lactoferricin B, an antimicrobial peptide derived from bovine lactoferrin. Biochemistry. 1998;37(12):4288-98. 107. Ulvatne H, Samuelsen O, Haukland HH, Kramer M, Vorland LH. Lactoferricin B inhibits bacterial macromolecular synthesis in Escherichia coli and Bacillus subtilis. FEMS microbiology letters. 2004;237(2):377-84. 108. Hagiwara D, Yamashino T, Mizuno T. A Genome-wide view of the Escherichia coli BasS-BasR two-component system implicated in iron-responses. Bioscience, biotechnology, and biochemistry. 2004;68(8):1758-67. 109. Schnapp D, Kemp GD, Smith VJ. Purification and characterization of a proline-rich antibacterial peptide, with sequence similarity to bactenecin-7, from the haemocytes of the shore crab, Carcinus maenas. European journal of biochemistry / FEBS. 1996;240(3):532-9. 285 110. Podda E, Benincasa M, Pacor S, Micali F, Mattiuzzo M, Gennaro R, et al. Dual mode of action of Bac7, a proline-rich antibacterial peptide. Biochim Biophys Acta. 2006;1760(11):1732-40. 111. Mattiuzzo M, Bandiera A, Gennaro R, Benincasa M, Pacor S, Antcheva N, et al. Role of the Escherichia coli SbmA in the antimicrobial activity of proline-rich peptides. Mol Microbiol. 2007;66(1):151-63. 112. Scocchi M, Lüthy C, Decarli P, Mignogna G, Christen P, Gennaro R. The Proline-rich Antibacterial Peptide Bac7 Binds to and Inhibits in vitro the Molecular Chaperone DnaK. International Journal of Peptide Research and Therapeutics. 2009;15(2):147-55. 113. Mardirossian M, Grzela R, Giglione C, Meinnel T, Gennaro R, Mergaert P, et al. The host antimicrobial peptide Bac71-35 binds to bacterial ribosomal proteins and inhibits protein synthesis. Chem Biol. 2014;21(12):1639-47. 114. Agerberth B, Lee JY, Bergman T, Carlquist M, Boman HG, Mutt V, et al. Amino acid sequence of PR-39. Isolation from pig intestine of a new member of the family of proline-arginine-rich antibacterial peptides. Eur J Biochem. 1991;202(3):849-54. 115. Shi J, Ross CR, Chengappa MM, Blecha F. Identification of a proline-arginine-rich antibacterial peptide from neutrophils that is analogous to PR-39, an antibacterial peptide from the small intestine. J Leukoc Biol. 1994;56(6):807-11. 116. Pranting M, Negrea A, Rhen M, Andersson DI. Mechanism and fitness costs of PR-39 resistance in Salmonella enterica serovar Typhimurium LT2. Antimicrob Agents Chemother. 2008;52(8):2734-41. 286 117. Boman HG, Agerberth B, Boman A. Mechanisms of action on Escherichia coli of cecropin P1 and PR-39, two antibacterial peptides from pig intestine. Infect Immun. 1993;61(7):2978-84. 118. Zanetti M. Cathelicidins, multifunctional peptides of the innate immunity. J Leukoc Biol. 2004;75(1):39-48. 119. Sang Y, Blecha F. Porcine host defense peptides: expanding repertoire and functions. Dev Comp Immunol. 2009;33(3):334-43. 120. Cole AM, Weis P, Diamond G. Isolation and characterization of pleurocidin, an antimicrobial peptide in the skin secretions of winter flounder. J Biol Chem. 1997;272(18):12008-13. 121. Mor A, Nguyen VH, Delfour A, Migliore-Samour D, Nicolas P. Isolation, amino acid sequence, and synthesis of dermaseptin, a novel antimicrobial peptide of amphibian skin. Biochemistry. 1991;30(36):8824-30. 122. Giuliani A, Pirri G, Nicoletto S. Antimicrobial peptides: an overview of a promising class of therapeutics. centeurjbiol. 2007;2(1):1-33. 123. Patrzykat A, Friedrich CL, Zhang L, Mendoza V, Hancock RE. Sublethal concentrations of pleurocidin-derived antimicrobial peptides inhibit macromolecular synthesis in Escherichia coli. Antimicrob Agents Chemother. 2002;46(3):605-14. 124. Shai Y. Molecular recognition between membrane-spanning polypeptides. Trends Biochem Sci. 1995;20(11):460-4. 125. Pushpanathan M, Gunasekaran P, Rajendhran J. Antimicrobial peptides: versatile biological properties. Int J Pept. 2013;2013:675391. 287 126. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415(6870):389-95. 127. Kang HK, Kim C, Seo CH, Park Y. The therapeutic applications of antimicrobial peptides (AMPs): a patent review. J Microbiol. 2017;55(1):1-12. 128. Mahlapuu M, Hakansson J, Ringstad L, Bjorn C. Antimicrobial Peptides: An Emerging Category of Therapeutic Agents. Front Cell Infect Microbiol. 2016;6:194. 129. Fox JL. Antimicrobial peptides stage a comeback. Nat Biotechnol. 2013;31(5):379-82. 130. Lehrer RI, Ganz T. Cathelicidins: a family of endogenous antimicrobial peptides. Curr Opin Hematol. 2002;9(1):18-22. 131. Yang ST, Shin SY, Hahm KS, Kim JI. Different modes in antibiotic action of tritrpticin analogs, cathelicidin-derived Trp-rich and Pro/Arg-rich peptides. Biochim Biophys Acta. 2006;1758(10):1580-6. 132. Yang ST, Yub Shin SY, Kim YC, Kim Y, Hahm KS, Kim JI. Conformation-dependent antibiotic activity of tritrpticin, a cathelicidin-derived antimicrobial peptide. Biochem Biophys Res Commun. 2002;296(5):1044-50. 133. Schibli DJ, Hwang PM, Vogel HJ. Structure of the antimicrobial peptide tritrpticin bound to micelles: a distinct membrane-bound peptide fold. Biochemistry. 1999;38(51):16749-55. 134. Powers JP, Tan A, Ramamoorthy A, Hancock RE. Solution structure and interaction of the antimicrobial polyphemusins with lipid membranes. Biochemistry. 2005;44(47):15504-13. 288 135. Miyata T, Tokunaga F, Yoneya T, Yoshikawa K, Iwanaga S, Niwa M, et al. Antimicrobial peptides, isolated from horseshoe crab hemocytes, tachyplesin II, and polyphemusins I and II: chemical structures and biological activity. J Biochem. 1989;106(4):663-8. 136. Zhang L, Scott MG, Yan H, Mayer LD, Hancock RE. Interaction of polyphemusin I and structural analogs with bacterial membranes, lipopolysaccharide, and lipid monolayers. Biochemistry. 2000;39(47):14504-14. 137. Masuda M, Nakashima H, Ueda T, Naba H, Ikoma R, Otaka A, et al. A novel anti-HIV synthetic peptide, T-22 ([Tyr5,12,Lys7]-polyphemusin II). Biochemical and biophysical research communications. 1992;189(2):845-50. 138. Powers JP, Martin MM, Goosney DL, Hancock RE. The antimicrobial peptide polyphemusin localizes to the cytoplasm of Escherichia coli following treatment. Antimicrob Agents Chemother. 2006;50(4):1522-4. 139. Bohmova E, Machova D, Pechar M, Pola R, Venclikova K, Janouskova O, et al. Cell-penetrating peptides: a useful tool for the delivery of various cargoes into cells. Physiol Res. 2018;67(Supplementum 2):S267-S79. 140. Guidotti G, Brambilla L, Rossi D. Cell-Penetrating Peptides: From Basic Research to Clinics. Trends Pharmacol Sci. 2017;38(4):406-24. 141. Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem. 1994;269(14):10444-50. 289 142. Liu C, Tai L, Zhang W, Wei G, Pan W, Lu W. Penetratin, a potentially powerful absorption enhancer for noninvasive intraocular drug delivery. Mol Pharm. 2014;11(4):1218-27. 143. Dom G, Shaw-Jackson C, Matis C, Bouffioux O, Picard JJ, Prochiantz A, et al. Cellular uptake of Antennapedia Penetratin peptides is a two-step process in which phase transfer precedes a tryptophan-dependent translocation. Nucleic Acids Res. 2003;31(2):556-61. 144. Bahnsen JS, Franzyk H, Sandberg-Schaal A, Nielsen HM. Antimicrobial and cell-penetrating properties of penetratin analogs: effect of sequence and secondary structure. Biochim Biophys Acta. 2013;1828(2):223-32. 145. Ebbensgaard A, Mordhorst H, Overgaard MT, Nielsen CG, Aarestrup FM, Hansen EB. Comparative Evaluation of the Antimicrobial Activity of Different Antimicrobial Peptides against a Range of Pathogenic Bacteria. PLoS One. 2015;10(12):e0144611. 146. Hilpert K, McLeod B, Yu J, Elliott MR, Rautenbach M, Ruden S, et al. Short cationic antimicrobial peptides interact with ATP. Antimicrob Agents Chemother. 2010;54(10):4480-3. 147. Khurshid Z, Naseem M, Sheikh Z, Najeeb S, Shahab S, Zafar MS. Oral antimicrobial peptides: Types and role in the oral cavity. Saudi Pharm J. 2016;24(5):515-24. 148. Raj PA, Marcus E, Sukumaran DK. Structure of human salivary histatin 5 in aqueous and nonaqueous solutions. Biopolymers. 1998;45(1):51-67. 149. Xu T, Levitz SM, Diamond RD, Oppenheim FG. Anticandidal activity of major human salivary histatins. Infect Immun. 1991;59(8):2549-54. 290 150. Puri S, Edgerton M. How does it kill?: understanding the candidacidal mechanism of salivary histatin 5. Eukaryot Cell. 2014;13(8):958-64. 151. Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44-57. 152. Laitinen OH, Hytonen VP, Nordlund HR, Kulomaa MS. Genetically engineered avidins and streptavidins. Cell Mol Life Sci. 2006;63(24):2992-3017. 153. Tytgat HL, Schoofs G, Driesen M, Proost P, Van Damme EJ, Vanderleyden J, et al. Endogenous biotin-binding proteins: an overlooked factor causing false positives in streptavidin-based protein detection. Microb Biotechnol. 2015;8(1):164-8. 154. Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981;29(4):577-80. 155. Zempleni J, Hassan YI, Wijeratne SS. Biotin and biotinidase deficiency. Expert Rev Endocrinol Metab. 2008;3(6):715-24. 156. Almohanna HM, Ahmed AA, Tsatalis JP, Tosti A. The Role of Vitamins and Minerals in Hair Loss: A Review. Dermatol Ther (Heidelb). 2019;9(1):51-70. 157. Bonjour JP. Biotin in man′s nutrition and therapy -- a review. Int J Vitam Nutr Res. 1977;47(2):107-18. 158. Said HM, Ortiz A, McCloud E, Dyer D, Moyer MP, Rubin S. Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared with pantothenic acid. Am J Physiol. 1998;275(5):C1365-71. 159. Zempleni J, Mock DM. Biotin biochemistry and human requirements. J Nutr Biochem. 1999;10(3):128-38. 291 160. Tong L. Structure and function of biotin-dependent carboxylases. Cell Mol Life Sci. 2013;70(5):863-91. 161. Zempleni J. Uptake, localization, and noncarboxylase roles of biotin. Annu Rev Nutr. 2005;25:175-96. 162. Ingaramo M, Beckett D. Biotinylation, a post-translational modification controlled by the rate of protein-protein association. J Biol Chem. 2011;286(15):13071-8. 163. Jitrapakdee S, Wallace JC. The biotin enzyme family: conserved structural motifs and domain rearrangements. Curr Protein Pept Sci. 2003;4(3):217-29. 164. Bagautdinov B, Matsuura Y, Bagautdinova S, Kunishima N. Protein biotinylation visualized by a complex structure of biotin protein ligase with a substrate. J Biol Chem. 2008;283(21):14739-50. 165. Wolf B. Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have". Genet Med. 2012;14(6):565-75. 166. Wolf B, Heard GS, McVoy JR, Raetz HM. Biotinidase deficiency: the possible role of biotinidase in the processing of dietary protein-bound biotin. J Inherit Metab Dis. 1984;7 Suppl 2:121-2. 167. Choi-Rhee E, Cronan JE. The biotin carboxylase-biotin carboxyl carrier protein complex of Escherichia coli acetyl-CoA carboxylase. J Biol Chem. 2003;278(33):30806-12. 168. Kim HS, Hoja U, Stolz J, Sauer G, Schweizer E. Identification of the tRNA-binding protein Arc1p as a novel target of in vivo biotinylation in Saccharomyces cerevisiae. J Biol Chem. 2004;279(41):42445-52. 169. Berdy J. Bioactive microbial metabolites. J Antibiot (Tokyo). 2005;58(1):1-26. 292 170. Clardy J, Fischbach MA, Currie CR. The natural history of antibiotics. Curr Biol. 2009;19(11):R437-41. 171. Jones KE, Patel NG, Levy MA, Storeygard A, Balk D, Gittleman JL, et al. Global trends in emerging infectious diseases. Nature. 2008;451(7181):990-3. 172. Levy SB, Marshall B. Antibacterial resistance worldwide: causes, challenges and responses. Nat Med. 2004;10(12 Suppl):S122-9. 173. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1-12. 174. Spellberg B. The future of antibiotics. Crit Care. 2014;18(3):228. 175. Kapoor G, Saigal S, Elongavan A. Action and resistance mechanisms of antibiotics: A guide for clinicians. J Anaesthesiol Clin Pharmacol. 2017;33(3):300-5. 176. Coates AR, Hu Y. Novel approaches to developing new antibiotics for bacterial infections. Br J Pharmacol. 2007;152(8):1147-54. 177. Coates AR, Halls G, Hu Y. Novel classes of antibiotics or more of the same? Br J Pharmacol. 2011;163(1):184-94. 178. Miller JR, Waldrop GL. Discovery of novel antibacterials. Expert Opin Drug Discov. 2010;5(2):145-54. 179. Bandow JE, Brotz H, Leichert LI, Labischinski H, Hecker M. Proteomic approach to understanding antibiotic action. Antimicrob Agents Chemother. 2003;47(3):948-55. 180. Navid A. Applications of system-level models of metabolism for analysis of bacterial physiology and identification of new drug targets. Brief Funct Genomics. 2011;10(6):354-64. 293 181. Panjkovich A, Gibert I, Daura X. antibacTR: dynamic antibacterial-drug-target ranking integrating comparative genomics, structural analysis and experimental annotation. BMC Genomics. 2014;15:36. 182. Gupta EK, Ito MK. Lovastatin and extended-release niacin combination product: the first drug combination for the management of hyperlipidemia. Heart disease. 2002;4(2):124-37. 183. Larder BA, Kemp SD, Harrigan PR. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science. 1995;269(5224):696-9. 184. Zimmermann GR, Lehar J, Keith CT. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug discovery today. 2007;12(1-2):34-42. 185. Loewe S. The problem of synergism and antagonism of combined drugs. Arzneimittel-Forschung. 1953;3(6):285-90. 186. I. BC. The toxicity of poisons applied jointly. Annals of applied biology. 1939;26:30. 187. Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer research. 2010;70(2):440-6. 188. Cokol M, Chua HN, Tasan M, Mutlu B, Weinstein ZB, Suzuki Y, et al. Systematic exploration of synergistic drug pairs. Molecular systems biology. 2011;7:544. 189. Hegreness M, Shoresh N, Damian D, Hartl D, Kishony R. Accelerated evolution of resistance in multidrug environments. Proc Natl Acad Sci U S A. 2008;105(37):13977-81. 190. Lehar J, Krueger AS, Avery W, Heilbut AM, Johansen LM, Price ER, et al. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nature biotechnology. 2009;27(7):659-66. 294 191. Brumfitt W, Salton MR, Hamilton-Miller JM. Nisin, alone and combined with peptidoglycan-modulating antibiotics: activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. The Journal of antimicrobial chemotherapy. 2002;50(5):731-4. 192. McCafferty DG, Cudic P, Yu MK, Behenna DC, Kruger R. Synergy and duality in peptide antibiotic mechanisms. Current opinion in chemical biology. 1999;3(6):672-80. 193. Naghmouchi K, Le Lay C, Baah J, Drider D. Antibiotic and antimicrobial peptide combinations: synergistic inhibition of Pseudomonas fluorescens and antibiotic-resistant variants. Research in microbiology. 2012;163(2):101-8. 194. Davis BD. Mechanism of bactericidal action of aminoglycosides. Microbiological reviews. 1987;51(3):341-50. 195. Plotz PH, Davis BD. Synergism between streptomycin and penicillin: a proposed mechanism. Science. 1962;135(3508):1067-8. 196. Cottagnoud P, Cottagnoud M, Tauber MG. Vancomycin acts synergistically with gentamicin against penicillin-resistant pneumococci by increasing the intracellular penetration of gentamicin. Antimicrobial agents and chemotherapy. 2003;47(1):144-7. 197. Dinos GP, Connell SR, Nierhaus KH, Kalpaxis DL. Erythromycin, roxithromycin, and clarithromycin: use of slow-binding kinetics to compare their in vitro interaction with a bacterial ribosomal complex active in peptide bond formation. Molecular pharmacology. 2003;63(3):617-23. 198. Iscla I, Wray R, Wei S, Posner B, Blount P. Streptomycin potency is dependent on MscL channel expression. Nat Commun. 2014;5:4891. 295 199. Jones RN, Ballow CH, Biedenbach DJ, Deinhart JA, Schentag JJ. Antimicrobial activity of quinupristin-dalfopristin (RP 59500, Synercid) tested against over 28,000 recent clinical isolates from 200 medical centers in the United States and Canada. Diagn Microbiol Infect Dis. 1998;31(3):437-51. 200. Mizoguchi J, Suginaka H, Kotani S. Mechanism of synergistic action of a combination of ampicillin and dicloxacillin against a beta-lactamase-producing strain of Citrobacter freundii. Antimicrob Agents Chemother. 1979;16(4):439-43. 201. Nichols RJ, Sen S, Choo YJ, Beltrao P, Zietek M, Chaba R, et al. Phenotypic landscape of a bacterial cell. Cell. 2011;144(1):143-56. 202. Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol Syst Biol. 2006;2:2006 0008. 203. Claeys KC, Fiorvento AD, Rybak MJ. A Review of Novel Combinations of Colistin and Lipopeptide or Glycopeptide Antibiotics for the Treatment of Multidrug-Resistant Acinetobacter baumannii. Infect Dis Ther. 2014;3(2):69-81. 204. Haaber J, Friberg C, McCreary M, Lin R, Cohen SN, Ingmer H. Reversible antibiotic tolerance induced in Staphylococcus aureus by concurrent drug exposure. MBio. 2015;6(1). 205. Singh N, Yeh PJ. Suppressive drug combinations and their potential to combat antibiotic resistance. J Antibiot (Tokyo). 2017;70(11):1033-42. 206. Xu KJ, Song J, Zhao XM. The drug cocktail network. BMC systems biology. 2012;6 Suppl 1:S5. 296 207. Bollenbach T. Antimicrobial interactions: mechanisms and implications for drug discovery and resistance evolution. Curr Opin Microbiol. 2015;27:1-9. 208. Ho YH, Shah P, Chen YW, Chen CS. Systematic analysis of intracellular targeting antimicrobial peptide Bac 7, PR-39, P-Der and Lfcin B, using E. coli proteome microarrays. Mol Cell Proteomics. 2015:under submission. 209. Caetano-Anolles K, Caetano-Anolles G. Structural phylogenomics reveals gradual evolutionary replacement of abiotic chemistries by protein enzymes in purine metabolism. PLoS One. 2013;8(3):e59300. 210. Low CY, Rotstein C. Emerging fungal infections in immunocompromised patients. F1000 Med Rep. 2011;3:14. 211. Scorzoni L, de Paula ESAC, Marcos CM, Assato PA, de Melo WC, de Oliveira HC, et al. Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis. Front Microbiol. 2017;8:36. 212. McCarthy MW, Kontoyiannis DP, Cornely OA, Perfect JR, Walsh TJ. Novel Agents and Drug Targets to Meet the Challenges of Resistant Fungi. J Infect Dis. 2017;216(suppl_3):S474-S83. 213. Bechara C, Sagan S. Cell-penetrating peptides: 20 years later, where do we stand? FEBS Lett. 2013;587(12):1693-702. 214. Bellamy W, Takase M, Wakabayashi H, Kawase K, Tomita M. Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine lactoferrin. J Appl Bacteriol. 1992;73(6):472-9. 297 215. Chan DI, Prenner EJ, Vogel HJ. Tryptophan- and arginine-rich antimicrobial peptides: structures and mechanisms of action. Biochim Biophys Acta. 2006;1758(9):1184-202. 216. Fernandes KE, Carter DA. The Antifungal Activity of Lactoferrin and Its Derived Peptides: Mechanisms of Action and Synergy with Drugs against Fungal Pathogens. Front Microbiol. 2017;8:2. 217. Wakabayashi H, Hiratani T, Uchida K, Yamaguchi H. Antifungal Spectrum and Fungicidal Mechanism of an N-Terminal Peptide of Bovine Lactoferrin. J Infect Chemother. 1996;1(3):185-9. 218. Koshlukova SE, Lloyd TL, Araujo MW, Edgerton M. Salivary histatin 5 induces non-lytic release of ATP from Candida albicans leading to cell death. J Biol Chem. 1999;274(27):18872-9. 219. Helmerhorst EJ, Breeuwer P, van′t Hof W, Walgreen-Weterings E, Oomen LC, Veerman EC, et al. The cellular target of histatin 5 on Candida albicans is the energized mitochondrion. J Biol Chem. 1999;274(11):7286-91. 220. Baev D, Li XS, Dong J, Keng P, Edgerton M. Human salivary histatin 5 causes disordered volume regulation and cell cycle arrest in Candida albicans. Infect Immun. 2002;70(9):4777-84. 221. Baev D, Rivetta A, Vylkova S, Sun JN, Zeng GF, Slayman CL, et al. The TRK1 potassium transporter is the critical effector for killing of Candida albicans by the cationic protein, Histatin 5. J Biol Chem. 2004;279(53):55060-72. 298 222. Koshlukova SE, Araujo MW, Baev D, Edgerton M. Released ATP is an extracellular cytotoxic mediator in salivary histatin 5-induced killing of Candida albicans. Infect Immun. 2000;68(12):6848-56. 223. Mania D, Hilpert K, Ruden S, Fischer R, Takeshita N. Screening for antifungal peptides and their modes of action in Aspergillus nidulans. Appl Environ Microbiol. 2010;76(21):7102-8. 224. Masman MF, Rodriguez AM, Raimondi M, Zacchino SA, Luiten PG, Somlai C, et al. Penetratin and derivatives acting as antifungal agents. Eur J Med Chem. 2009;44(1):212-28. 225. Garibotto FM, Garro AD, Rodriguez AM, Raimondi M, Zacchino SA, Perczel A, et al. Penetratin analogues acting as antifungal agents. Eur J Med Chem. 2011;46(1):370-7. 226. Helmerhorst EJ, Troxler RF, Oppenheim FG. The human salivary peptide histatin 5 exerts its antifungal activity through the formation of reactive oxygen species. Proc Natl Acad Sci U S A. 2001;98(25):14637-42. 227. Bhattacharya S, Esquivel BD, White TC. Overexpression or Deletion of Ergosterol Biosynthesis Genes Alters Doubling Time, Response to Stress Agents, and Drug Susceptibility in Saccharomyces cerevisiae. MBio. 2018;9(4). 228. Alcazar-Fuoli L, Mellado E. Ergosterol biosynthesis in Aspergillus fumigatus: its relevance as an antifungal target and role in antifungal drug resistance. Front Microbiol. 2012;3:439. 299 229. Lum PY, Armour CD, Stepaniants SB, Cavet G, Wolf MK, Butler JS, et al. Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell. 2004;116(1):121-37. 230. Ryder NS. Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol. 1992;126 Suppl 39:2-7. 231. Li XS, Sun JN, Okamoto-Shibayama K, Edgerton M. Candida albicans cell wall ssa proteins bind and facilitate import of salivary histatin 5 required for toxicity. J Biol Chem. 2006;281(32):22453-63. 232. Sun JN, Li W, Jang WS, Nayyar N, Sutton MD, Edgerton M. Uptake of the antifungal cationic peptide Histatin 5 by Candida albicans Ssa2p requires binding to non-conventional sites within the ATPase domain. Mol Microbiol. 2008;70(5):1246-60. 233. Kumar R, Chadha S, Saraswat D, Bajwa JS, Li RA, Conti HR, et al. Histatin 5 uptake by Candida albicans utilizes polyamine transporters Dur3 and Dur31 proteins. J Biol Chem. 2011;286(51):43748-58. 234. Daum G. Lipids of mitochondria. Biochim Biophys Acta. 1985;822(1):1-42. 235. Denning DW, Perlin DS, Muldoon EG, Colombo AL, Chakrabarti A, Richardson MD, et al. Delivering on Antimicrobial Resistance Agenda Not Possible without Improving Fungal Diagnostic Capabilities. Emerg Infect Dis. 2017;23(2):177-83. 236. Leekha S, Terrell CL, Edson RS. General principles of antimicrobial therapy. Mayo Clin Proc. 2011;86(2):156-67. 237. Imanpour S, Nwaiwu O, McMaughan DK, DeSalvo B, Bashir A. Factors associated with antibiotic prescriptions for the viral origin diseases in office-based practices, 2006-2012. JRSM Open. 2017;8(8):2054270417717668. 300 238. Ben-Ami R, Olshtain-Pops K, Krieger M, Oren I, Bishara J, Dan M, et al. Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection. Antimicrob Agents Chemother. 2012;56(5):2518-23. 239. Clark C, Drummond RA. The Hidden Cost of Modern Medical Interventions: How Medical Advances Have Shaped the Prevalence of Human Fungal Disease. Pathogens. 2019;8(2). 240. Allen U. Antifungal agents for the treatment of systemic fungal infections in children. Paediatr Child Health. 2010;15(9):603-15. 241. Hida S, Yoshida M, Nakabayashi I, Miura NN, Adachi Y, Ohno N. Anti-fungal activity of sulfamethoxazole toward Aspergillus species. Biol Pharm Bull. 2005;28(5):773-8. 242. Bayly AM, Berglez JM, Patel O, Castelli LA, Hankins EG, Coloe P, et al. Folic acid utilisation related to sulfa drug resistance in Saccharomyces cerevisiae. FEMS Microbiol Lett. 2001;204(2):387-90. 243. Abou-Eisha A, Creus A, Marcos R. Genotoxic evaluation of the antimicrobial drug, trimethoprim, in cultured human lymphocytes. Mutat Res. 1999;440(2):157-62. 244. Patel O, Karnik K, Macreadie IG. Over-production of dihydrofolate reductase leads to sulfa-dihydropteroate resistance in yeast. FEMS Microbiol Lett. 2004;236(2):301-5. 245. Patel OG, Mberu EK, Nzila AM, Macreadie IG. Sulfa drugs strike more than once. Trends Parasitol. 2004;20(1):1-3. 246. Tong AH, Lesage G, Bader GD, Ding H, Xu H, Xin X, et al. Global mapping of the yeast genetic interaction network. Science. 2004;303(5659):808-13. 301 247. Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH. Integrating genetic approaches into the discovery of anticancer drugs. Science. 1997;278(5340):1064-8. 248. Kaelin WG, Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5(9):689-98. 249. Costanzo M, Baryshnikova A, Bellay J, Kim Y, Spear ED, Sevier CS, et al. The genetic landscape of a cell. Science. 2010;327(5964):425-31. 250. Hillenmeyer ME, Fung E, Wildenhain J, Pierce SE, Hoon S, Lee W, et al. The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science. 2008;320(5874):362-5. 251. Collins SR, Miller KM, Maas NL, Roguev A, Fillingham J, Chu CS, et al. Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map. Nature. 2007;446(7137):806-10. 252. Bandyopadhyay S, Mehta M, Kuo D, Sung MK, Chuang R, Jaehnig EJ, et al. Rewiring of genetic networks in response to DNA damage. Science. 2010;330(6009):1385-9. 253. Zinovyev A, Kuperstein I, Barillot E, Heyer WD. Synthetic lethality between gene defects affecting a single non-essential molecular pathway with reversible steps. PLoS Comput Biol. 2013;9(4):e1003016. 254. Ooi SL, Pan X, Peyser BD, Ye P, Meluh PB, Yuan DS, et al. Global synthetic-lethality analysis and yeast functional profiling. Trends Genet. 2006;22(1):56-63. 255. Nijman SM. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett. 2011;585(1):1-6. 302 256. Guo J, Liu H, Zheng J. SynLethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets. Nucleic Acids Res. 2016;44(D1):D1011-7. 257. Wakiec R, Gabriel I, Prasad R, Becker JM, Payne JW, Milewski S. Enhanced susceptibility to antifungal oligopeptides in yeast strains overexpressing ABC multidrug efflux pumps. Antimicrob Agents Chemother. 2008;52(11):4057-63. 258. Koutelou E, Hirsch CL, Dent SY. Multiple faces of the SAGA complex. Curr Opin Cell Biol. 2010;22(3):374-82. 259. Sermwittayawong D, Tan S. SAGA binds TBP via its Spt8 subunit in competition with DNA: implications for TBP recruitment. EMBO J. 2006;25(16):3791-800. 260. Wood A, Krogan NJ, Dover J, Schneider J, Heidt J, Boateng MA, et al. Bre1, an E3 ubiquitin ligase required for recruitment and substrate selection of Rad6 at a promoter. Mol Cell. 2003;11(1):267-74. 261. Weake VM, Workman JL. Histone ubiquitination: triggering gene activity. Mol Cell. 2008;29(6):653-63. 262. Samara NL, Datta AB, Berndsen CE, Zhang X, Yao T, Cohen RE, et al. Structural insights into the assembly and function of the SAGA deubiquitinating module. Science. 2010;328(5981):1025-9. 263. Zhang Y. Transcriptional regulation by histone ubiquitination and deubiquitination. Genes Dev. 2003;17(22):2733-40. 264. Ocana A, Pandiella A. Novel Synthetic Lethality Approaches for Drug Combinations and Early Drug Development. Curr Cancer Drug Targets. 2017;17(1):48-52. 303 265. Trosset JY, Carbonell P. Synergistic Synthetic Biology: Units in Concert. Front Bioeng Biotechnol. 2013;1:11. 266. Campbell J, Singh AK, Santa Maria JP, Jr., Kim Y, Brown S, Swoboda JG, et al. Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosyntheses in Staphylococcus aureus. ACS Chem Biol. 2011;6(1):106-16. 267. Rodenstein DO. Assessment of uvulopalatopharyngoplasty for the treatment of sleep apnea syndrome. Sleep. 1992;15(6 Suppl):S56-62. 268. Blount ZD. The unexhausted potential of E. coli. Elife. 2015;4. 269. Botstein D, Chervitz SA, Cherry JM. Yeast as a model organism. Science. 1997;277(5330):1259-60. 270. Karathia H, Vilaprinyo E, Sorribas A, Alves R. Saccharomyces cerevisiae as a model organism: a comparative study. PLoS One. 2011;6(2):e16015. 271. Kitagawa M, Ara T, Arifuzzaman M, Ioka-Nakamichi T, Inamoto E, Toyonaga H, et al. Complete set of ORF clones of Escherichia coli ASKA library (a complete set of E. coli K-12 ORF archive): unique resources for biological research. DNA Res. 2005;12(5):291-9. 272. Yousuf FA, Yousuf Z, Iqbal J, Siddiqui R, Khan H, Khan NA. Interactions of neuropathogenic Escherichia coli K1 (RS218) and its derivatives lacking genomic islands with phagocytic Acanthamoeba castellanii and nonphagocytic brain endothelial cells. Biomed Res Int. 2014;2014:265424. 304 273. Lu KY, Tao SC, Yang TC, Ho YH, Lee CH, Lin CC, et al. Profiling lipid-protein interactions using nonquenched fluorescent liposomal nanovesicles and proteome microarrays. Mol Cell Proteomics. 2012;11(11):1177-90. 274. Cherry JM, Hong EL, Amundsen C, Balakrishnan R, Binkley G, Chan ET, et al. Saccharomyces Genome Database: the genomics resource of budding yeast. Nucleic Acids Res. 2012;40(Database issue):D700-5. 275. UniProt Consortium T. UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2018;46(5):2699.
指導教授	徐沺陳健生(Tien Hsu Chien-Sheng (Jason) Chen)	審核日期	2019-8-24
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