リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「真菌の転写因子Yap1活性化によるミトコンドリアの抗酸化および薬剤耐性の研究」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

真菌の転写因子Yap1活性化によるミトコンドリアの抗酸化および薬剤耐性の研究

鵜飼 雄太 大阪府立大学 DOI:info:doi/10.24729/00017531

2021.11.19

概要

深在性真菌症は臓器移植や抗がん剤治療などにより免疫抑制状態にある患者に発症し得る致死性の高い難治性感染症である.健常人では感染,発症することが稀な日和見感染菌のカンジダ属菌やアスペルギルス属菌が主な起因菌となる.近年では,インフルエンザウイルス感染症や新型コロナウイルス感染症(COVID-19)に罹患した後に,アスペルギルス症を発症する例が数多く報告されており,その疫学や発症機序が注目を集めている(1-10).高度にグローバル化した現代において,2009 年の新型インフルエンザや 2019 年の COVID-19 といった呼吸器感染症のパンデミックが現実の脅威となっているなか,それに付随して環境中に普遍的に存在するアスペルギルスが引き起こす重篤な呼吸器感染症が,これまでよりも身近な感染症になりつつあることが危惧されている.

深在性真菌症の予防ならびに治療には抗真菌薬が用いられるが,国内で認可されている薬剤はアゾール系,ポリエン系,エキノキャンディン系ならびにフルシトシンの 4 系統であり,細菌感染症と比較して治療選択肢が限られている.各系統の代表的な薬剤名,標的分子,主な耐性機序を表 1 に示す.アゾール系薬とエキノキャンディン系薬は標的酵素の阻害によって抗真菌活性を発揮する.アゾール系薬は標的酵素の構造変化や増加によって薬剤耐性を示すことに加えて,低分子阻害剤であることから薬剤排出ポンプの増加によっても薬剤耐性を示す.エキノキャンディン系薬は標的酵素の構造変化よって薬剤耐性を示すが,リポペプチドといった中分子であり,細胞内ではなく細胞膜上で酵素阻害作用を示すことから,薬剤排出ポンプの影響を受けない.ポリエン系薬は細胞膜成分のエルゴステロールに結合し,細胞膜上にポアを形成して真菌の細胞内容物を漏出させることにより殺真菌活性を発揮する.エルゴステロール合成系の変化によってポリエン系薬が結合しにくいステロールが生成されると薬剤耐性を示すが,耐性株の発生頻度は稀であり,病原性も低下することから医療上の問題にはなっていない.フルシトシン系薬は,細胞内でフルオロウラシルに変換されたのち,核酸アナログとして核酸合成系を阻害することにより抗真菌活性を発揮する.フルオロウラシルに変換する酵素の機能が欠失した場合に薬剤耐性を示し,耐性出現頻度が高いことから,近年では単剤で使用されることはなく,ポリエン系薬と併用して使用されることが多い.

表 1. 抗真菌薬の系統毎の特徴(モダンメディア 56 巻 6 号 2010改変)

カンジダ属菌は病原性酵母であり,生化学的,分子細胞生物学的な研究が高度に進展している出芽酵母と多くの共通点を持つことから,アゾール系薬やエキノキャンディン系薬に対する耐性機序の研究が進展し,標的遺伝子の変異に加えて,薬剤排出ポンプの影響などの詳細が明らかとなっている(11,12).近年では Candidaauris の抗真菌薬に対する多剤耐性が問題となっており(13-15),COVID-19 に伴うC. auris のアウトブレイクの発生例も報告されている(16,17).

アスペルギルス症についても,第一選択薬のアゾール系薬に対する耐性菌の出現と拡大が医療上の問題となってきている.アスペルギルスは環境中に生育する菌であることから,医療現場でのアゾール系薬への長期間の曝露によるものに加えて,農場で大量に散布されるアゾール系農薬への曝露によりアゾール耐性菌が出現することも問題視される理由である(18).アゾール系薬の標的酵素をコードするcyp51A 遺伝子の変異によって,アゾール系薬の結合力が低下すること,あるいは遺伝子発現が亢進することが主な耐性要因であるが,それらとは独立した転写因子の変異による耐性機序も報告されている(19).このような背景の中,薬剤耐性真菌の克服に寄与するために,酸化ストレス応答のマスター転写因子 Yap1 と薬剤耐性の関連性の解明を目指した研究を行うこととした.

真菌の転写因子 Yap1 の機能を図 1 に概略図で示す.Yap1 は自身が有する bZIPドメインにより,制御遺伝子のプロモーター領域の Yap1 結合配列(YRE)に結合することによって発現を誘導する.通常の環境では,自身が有する核外輸送シグナル(NES)に,核外輸送体の CRM1 が結合し,細胞質側に輸送されて核内に留まることができない.一方で,酸化ストレス条件下では,NES が酸化型に変化することによって CRM1 が結合できなくなり,その結果として Yap1 が恒常的に核内に局在することになる.核内に恒常的に局在する Yap1 は制御遺伝子の YRE に結合し,その遺伝子発現を誘導できるようになる.このように,酸化ストレス条件下でその機能が活性化する Yap1 と,抗真菌薬耐性の関連性を解明する手掛かりとして,本論文では先行研究で提示されていた 2 つの知見に着目した.

図 1. 酸化ストレス応答のマスター転写因子 Yap1 の機能

1 つ目は,アスペルギルスのミトコンドリア機能不全とアゾール耐性の関連性である.ミトコンドリアの機能不全がカルシウム伝達系やエルゴステロール合成系に影響を与えて,その結果として薬剤排出ポンプや標的遺伝子の発現が亢進することによりアゾール耐性が引き起こされる(20).すなわち,ミトコンドリアの機能不全を未然に防ぐことがアゾール耐性を抑制することになる.ミトコンドリアは真菌細胞内において,活性酸素種の主な発生器官であり,活性酸素種の除去がミトコンドリアの恒常性の維持には欠かせない.そこで,真菌のモデル生物であり,ミトコンドリア研究が進展している出芽酵母において,抗酸化酵素 Gpx2 に着目した.Gpx2 の遺伝子発現は,酸化ストレス条件下で転写因子 Yap1 により誘導される(21).また,Gpx2 遺伝子の欠損によってミトコンドリアの形態異常を引き起こすことが 知られている(22).第一章では Gpx2 のミトコンドリアにおける詳細な局在性を解明することにより,ミトコンドリアの恒常性維持に Yap1 により制御される Gpx2がどのように寄与し得るかを考察した.

2 つ目は,アスペルギルスの Yap1 の C 末端切断体がアゾール耐性を引き起こす現象である(23).出芽酵母の先行研究からこの C 末端切断体は Yap1 の恒常的な活性化を引き起こすと考えられるが,この恒常的な活性体は yap1 遺伝子の突然変異でも起こり得ると推察した.そこで,第二章において,Yap1 の突然変異体がアゾール耐性株として出現され得るか検証し,その耐性機序を詳細に解析した.さらに,第三章では新たな in vivo 薬効評価系を構築することにより,Yap1 活性化の突然変異体が in vivo におけるアゾール系薬の治療効果に影響を与えるかを検証した.これらの研究により,病原真菌における Yap1 活性化がアゾール耐性に及ぼす影響が明らかとなり,薬剤耐性真菌の克服の一助となることが期待される.

この論文で使われている画像

参考文献

1. Wauters J, Baar I, Meersseman P, Meersseman W, Dams K, Paep RD, Lagrou K, Wilmer A, Jorens P, Hermans G. 2012. Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study. Intensive Care Med. 38:1761–1768.

2. van de Veerdonk FL, Kolwijck E, Lestrade PP, Hodiamont CJ, Rijnders BJ, van Paassen J, Haas PJ, OliveiraDosSantos C, Kampinga GA, Bergmans DC, van Dijk K, de Haan AF, van Dissel J, van Hoeven HG, Verweij PE. 2017. Infuenza-associated aspergillosis in critically ill patients. Am J Respir Crit Care Med. 196:524–527.

3. Schauwvlieghe AFAD, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L,Van Tienen C, Lagrou K, Verweij PE, Van de Veerdonk FL, Gommers D, Spronk P, Bergmans DCJJ, Hoedemaekers A, Andrinopoulou ER, van denBerg CHSB, Jufermans NP, Hodiamont CJ, Vonk AG, Depuydt P, Boelens J, Wauters J, Dutch-Belgian Mycosis Study Group. 2018. Invasive aspergillosis in patients admitted to the intensive care unit with severe infuenza:a retrospective cohort study. Lancet Respir Med. 6:782–792.

4. Koehler P, Cornely OA, Böttiger BW, Dusse F, Eichenauer DA, Fuchs F, Hallek M, Jung N, Klein F, Persigehl T, Rybniker J, Kochanek M, Böll B, Shimabukuro-Vornhagen A. 2020. COVID-19 associated pulmonary aspergillosis. Mycoses. 63:528–34.

5. Alanio A, Dellière S, Fodil S, Bretagne S, Mégarbane B. 2020. Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19. Lancet Respir Med. 8:e48–49.

6. van Arkel ALE, Rijpstra TA, Belderbos HNA, van Wijngaarden P, Verweij PE, Bentvelsen RG. 2020. COVID-19 associated pulmonary aspergillosis. Am J Respir Crit Care Med. 202:132–35.

7. Nasir N, Farooqi J, Mahmood SF, Jabeen K. 2020. COVID-19-associated pulmonary aspergillosis (CAPA) in patients admitted with severe COVID-19 pneumonia: an observational study from Pakistan. Mycoses. 63:766–770.

8. Arastehfar A, Carvalho A, van de Veerdonk FL, Jenks JD, Koehler P, Krause R, Cornely OA, Perlin DS, Lass-Flörl C, and Hoenigl M. 2020. COVID-19 associated pulmonary aspergillosis (CAPA)—from immunology to treatment. J Fungi (Basel). 6:91.

9. Gangneux JP, Reizine F, Guegan H, Pinceaux K, Balch PL, Prat E, Pelletier R, Belaz S, Souhaitier ML, Tulzo YL, Seguin P, Lederlin M, Tadié JM, Robert-Gangneux F. 2020. Is the COVID-19 pandemic a good time to include aspergillus molecular detection to categorize aspergillosis in ICU patients? A monocentric experience. J Fungi (Basel). 10:105.

10. Meijer EFJ, Dofferhoff ASM, Hoiting O, Buil JB, Meis JF. 2020. Azole-resistant COVID-19-associated pulmonary aspergillosis in an immunocompetent host: a case report. J Fungi (Basel). 6:79.

11. Whaley SG, Berkow EL, Rybak JM, Nishimoto AT, Barker KS and Rogers PD. 2017. Azole antifungal resistance in Candida albicans and emerging Non-albicans Candida species. Front Microbiol. 7:2173

12. Perlin DS. 2015. Mechanisms of echinocandin antifungal drug resistance. Ann NY Acad Sci. 1354:1–11

13. Lockhart SR, Etienne KA, Vallabhaneni S, Farooqi J, Chowdhary A, Govender NP. 2017. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis. 64:134–140.

14. Sekyere JO. 2018. Candida auris: a systematic review and metaanalysis of current updates on an emerging multidrug-resistant pathogen. MicrobiologyOpen. 7:e00578.

15. Eyre DW, Sheppard AE, Madder H, Moir I, Moroney R, Quan TP. 2018. A Candida auris outbreak and its control in an intensive care setting. N Engl J Med. 379:1322– 1331.

16. Villanueva-Lozano H, Treviño-Rangel RJ, González GM, Ramírez-Elizondo MT, LaraMedrano R, Aleman-Bocanegra MC, Guajardo-Lara CE, Gaona-Chávez N, CastillejaLeal F, Torre-Amione G, Martínez-Reséndez MF. 2021. Outbreak of Candida auris infection in a COVID-19 hospital in Mexico. Clin Microbiol Infect. 27(5):813-816

17. Almeida JN, Elaine CF, Ferry H, Igor BB, Felicidade MP, Pedro HP, Magda MM, Regiane TS, Theun G and Arnaldo LC. 2021. Emergence of Candida auris in Brazil in a COVID-19 Intensive Care Unit. J Fungi. 7:220.

18. Berger S, El Chazli Y, Babu AF and Coste AT. 2017. Azole Resistance in Aspergillus fumigatus: A Consequence of Antifungal Use in Agriculture. Front Microbiol. 8:1024.

19. Hagiwara D, Watanabe A, Kamei K, Goldman GH. 2016. Epidemiological and genomic landscape of azole resistance mechanisms in Aspergillus fungi. Front Microbiol. 7:1–14.

20. Li Y, Zhang Y, Zhang C, Wang H, Wei X, Chen P, Lu L. 2020. Mitochondrial dysfunctions trigger the calcium signaling-dependent fungal multidrug resistance. Proc Natl Acad Sci. 117 (3):1711-1721

21. Tsuzi D, Maeta K, Takatsume Y, Izawa S, Inoue Y. 2004. Regulation of the yeast phospholipid hydroperoxide glutathione peroxidase GPX2 by oxidative stress is mediated by Yap1 and Skn7. FEBS Lett. 565(1-3):148-54.

22. Entian KD, Schuster T, Hegemann JH, Becher D, Feldmann H, Guldener U, Gotz R, Hansen M, Hollenberg CP, Jansen G, Kramer W, Klein S, Kotter P, Kricke J, Launhardt H, Mannhaupt G, Maierl A, Meyer P, Mewes W, Munder T, Niedenthal RK, Ramezani RM, Rohmer A, Romer A, Rose M, Schafer B, Siegler ML, Vetter J, Wilhelm N, Wolf K, Zimmermann FK, Zollner A, Hinnen A. 1999. Functional analysis of 150 deletion mutants in Saccharomyces cerevisiae by a systematic approach. Mol Gen Genet. 262:683–702.

23. Qiao J, Liu W, Li R. 2010. Truncated Afyap1 attenuates antifungal susceptibility of Aspergillus fumigatus to voriconazole and confers adaptation of the fungus to oxidative stress. Mycopathologia. 170:155–160.

24. Inoue Y, Matsuda T, Izawa S, Kimura A. 1999. Genetic analysis of glutathione peroxidase in oxidative stress response of Saccharomyces cerevisiae. J Biol Chem. 274: 27002–27009.

25. Ohdate T, Kita K, Inoue Y. 2010. Kinetics and redox regulation of Gpx1, an atypical 2Cys peroxiredoxin, in Saccharomyces cerevisiae. FEMS Yeast Res. 10:787–790.

26. Tanaka T, Izawa S, Inoue Y. 2005. GPX2, encoding a phospholipid hydroperoxide glutathione peroxidase homologue, codes for an atypical 2-Cys peroxiredoxin in Saccharomyces cerevisiae. J Biol Chem. 280:42078–42087.

27. Hofmann B, Hecht HJ, Flohé L, Peroxiredoxins. 2002. J Biol Chem. 383:347–364.

28. Delaunay A, Pflieger D, Barrault MB, Vinh J, Toledano MB. 2002. A thiol peroxidase is an H2O2 receptor and redox-transducer in gene activation. Cell. 111:471–481.

29. Naoe M, Ohwa Y, Ishikawa D, Ohshima C, Nishikawa S, Yamamoto H, Endo T. 2004. Identification of Tim40 that mediates protein sorting to the mitochondrial intermembrane space. J Biol Chem. 279:47815–47821.

30. Meisinger C, Sommer T, Pfanner N. 2000. Purification of Saccharomyces cerevisiae mitochondria devoid of microsomal and cytosolic contaminations. Anal. Biochem. 287:339–342.

31. Yamamoto H, Esaki M, Kanamori T, Tamura Y, Nishikawa S, Endo T. 2002. Tim50 is a subunit of the TIM23 complex that links protein translocation across the outer and inner mitochondrial membranes. Cell. 111:519–528.

32. Izawa S, Maeda K, Sugiyama K, Mano J, Inoue Y, Kimura A. 1999. Thioredoxin deficiency causes the constitutive activation of Yap1, an AP-1-like transcription factor in Saccharomyces cerevisiae. J Biol Chem. 274:28459–28465.

33. Avery AM, Avery SV. 2010. Saccharomyces cerevisiae expresses three phospholipids hydroperoxide glutathione peroxidases. J Biol Chem. 276:33730–33735.

34. Steinbach WJ, Marr KA, Anaissie EJ, Azie N, Quan SP, Meier-Kriesche HU, Apewokin S, Horn DL. 2012. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infect. 65:453–464.

35. Patterson TF, Thompson GR, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JAH, Bennett JE. 2016. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America. Clin Infect Dis. 63:e1–e60.

36. Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M, Baddley JW, Giladi M, Heinz WJ, Herbrecht R, Hope W, Karthaus M, Lee DG, Lortholary O, Morrison VA, Oren I, Selleslag D, Shoham S, Thompson GR, Lee M, Maher RM, Schmitt-Hoffmann AH, Zeiher B, Ullmann AJ. 2016. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): A phase 3, randomisedcontrolled, non-inferiority trial. Lancet. 387:760–769.

37. Denning DW, Venkateswarlu K, Oakley KL, Anderson MJ, Manning NJ, Stevens DA, Warnock DW, Kelly SL. 1997. Itraconazole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 41:1364–1368.

38. Chen J, Li H, Li R, Bu D, Wan Z. 2005. Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma. J Antimicrob Chemother. 55:31–37.

39. Verweij PE, Mellado E, and Melchers WJG. 2007. Multiple-triazole–resistant aspergillosis. N Engl J Med. 356:1481–1483.

40. Howard SJ, Cerar D, Anderson MJ, Albarrag A, Fisher MC, Pasqualotto AC, Laverdiere M, Arendrup MC, Perlin DS, Denning DW. 2009. Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis. 15:1068–1076.

41. van der Linden JWM, Arendrup MC, Warris A, Lagrou K, Pelloux H, Hauser PM, Chryssanthou E, Mellado E, Kidd SE, Tortorano AM, Dannaoui E, Gaustad P, Baddley JW, Uekötter A, Lass-Flörl C, Klimko N, Moore CB, Denning DW, Pasqualotto AC, Kibbler C, Arikan-Akdagli S, Andes D, Meletiadis J, Naumiuk L, Nucci M, Melchers WJG, Verweij PE. 2015. Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus. Emerg Infect Dis. 21:1041–1044.

42. Mann PA, Parmegiani RM, Wei SQ, Mendrick CA, Li X, Loebenberg D, DiDomenico B, Hare RS, Walker SS, McNicholas PM. 2003. Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14α-demethylase. Antimicrob Agents Chemother. 47:577–581.

43. Mellado E, Garcia-Effron G, Alcazar-Fuoli L, Cuenca-Estrella M, Rodriguez-Tudela JL. 2004. Substitutions at methionine 220 in the 14α-sterol demethylase (Cyp51A) of Aspergillus fumigatus are responsible for resistance in vitro to azole antifungal drugs. Antimicrob Agents Chemother. 48:2747–2750.

44. Alanio A, Sitterlé E, Liance M, Farrugia C, Foulet F, Botterel F, Hicheri Y, Cordonnier C, Costa JM, Bretagne S. 2011. Low prevalence of resistance to azoles in Aspergillus fumigatus in a French cohort of patients treated for haematological malignancies. J Antimicrob Chemother. 66:371–374.

45. Camps SMT, Van Der Linden JWM, Li Y, Kuijper EJ, Van Dissel JT, Verweij PE, Melchers WJG. 2012. Rapid induction of multiple resistance mechanisms in Aspergillus fumigatus during azole therapy: A case study and review of the literature. Antimicrob Agents Chemother. 56:10–16.

46. Natesan SK, Wu W, Cutright JL, Chandrasekar PH. 2012. In vitro-in vivo correlation of voriconazole resistance due to G448S mutation (cyp51A gene) in Aspergillus fumigatus. Diagn Microbiol Infect Dis. 74:272–277.

47. Mellado E, Garcia-Effron G, Alcázar-Fuoli L, Melchers WJG, Verweij PE, CuencaEstrella M, Rodriguez-Tudela JL. 2007. A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations. Antimicrob Agents Chemother. 51:1897–1904.

48. Snelders E, Van Der Lee HAL, Kuijpers J, Rijs AJMM, Varga J, Samson RA, Mellado E, Donders ART, Melchers WJG, Verweij PE. 2008. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med. 5:1629– 1637.

49. Vermeulen E, Maertens J, Schoemans H, Lagrou K. 2012. Azole-resistant Aspergillus fumigatus due to TR46/Y121F/T289A mutation emerging in Belgium, July 2012. Eurosurveillance. 17:3–5.

50. Chowdhary A, Sharma C, Kathuria S, Hagen F, Meis JF. 2014. Azole-resistant Aspergillus fumigatus with the environmental TR46/Y121F/T289A mutation in India. J Antimicrob Chemother. 69:555–557.

51. Wu CJ, Wang HC, Lee JC, Lo HJ, Dai CT, Chou PH, Ko WC, Chen YC. 2015. Azoleresistant Aspergillus fumigatus isolates carrying TR34/L98H mutations in Taiwan. Mycoses. 58:544–549.

52. Hagiwara D, Takahashi H, Fujimoto M, Sugahara M, Misawa Y, Gonoi T, Itoyama S, Watanabe A, Kamei K. 2016. Multi-azole resistant Aspergillus fumigatus harboring Cyp51A TR46/Y121F/T289A isolated in Japan. J Infect Chemother. 22:577–579.

53. Wiederhold NP, Gil G, Gutierrez F, Lindner JR, Albataineh MT, Mccarthy DI, Sanders C, Fan H, Fothergill AW, Sutton A. 2016. First detection of TR34 L98H and TR46 Y121F T289A Cyp51 mutations in Aspergillus fumigatus Isolates in the United States. J Clin Microbiol. 54:168–171.

54. Snelders E, Karawajczyk A, Verhoeven RJA, Venselaar H, Schaftenaar G, Verweij PE, Melchers WJG. 2011. The structure-function relationship of the Aspergillus fumigatus cyp51A L98H conversion by site-directed mutagenesis: The mechanism of L98H azole resistance. Fungal Genet Biol. 48:1062–1070.

55. Snelders E, Camps SMT, Karawajczyk A, Rijs AJMM, Zoll J, Verweij PE, Melchers WJG. 2015. Genotype-phenotype complexity of the TR46/Y121F/T289A cyp51A azole resistance mechanism in Aspergillus fumigatus. Fungal Genet Biol. 82:129–135.

56. Cannon RD, Lamping E, Holmes AR, Niimi K, Baret P V., Keniya M V., Tanabe K, Niimi M, Goffeau A, Monk BC. 2009. Efflux-mediated antifungal drug resistance. Clin Microbiol Rev. 22:291–321.

57. Fraczek MG, Bromley M, Buied A, Moore CB, Rajendran R, Rautemaa R, Ramage G, Denning DW, Bowyer P. 2013. The cdr1B efflux transporter is associated with noncyp51A-mediated itraconazole resistance in Aspergillus fumigatus. J Antimicrob Chemother. 68:1486–1496.

58. Paul S, Diekema D, Moye-Rowley WS. 2013. Contributions of Aspergillus fumigatus ATP-binding cassette transporter proteins to drug resistance and virulence. Eukaryot Cell. 12:1619–1628.

59. Meneau I, Coste AT, Sanglard D. 2016. Identification of Aspergillus fumigatus multidrug transporter genes and their potential involvement in antifungal resistance. Med Mycol. 54:616-627.

60. Hagiwara D, Miura D, Shimizu K, Paul S, Ohba A, Gonoi T, Watanabe A, Kamei K, Shintani T, Moye-Rowley WS, Kawamoto S, Gomi K. 2017. A novel Zn2-Cys6 transcription factor AtrR plays a key role in an azole resistance mechanism of Aspergillus fumigatus by co-regulating cyp51A and cdr1B Expressions. PLoS Pathogens. 13(1): e1006096.

61. Paul S, Diekema D, Moye-Rowley WS. 2017. Contributions of both ATP-binding cassette transporter and Cyp51A proteins are essential for azole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 61:1–10.

62. Baddley JW, Marr KA, Andes DR, Walsh TJ, Kauffman CA, Kontoyiannis DP, Ito JI, Balajee SA, Pappas PG, Moser SA. 2009. Patterns of susceptibility of Aspergillus isolates recovered from patients enrolled in the transplant-associated infection surveillance network. J Clin Microbiol. 47:3271–3275.

63. Krishnan S, Manavathu EK, Chandrasekar PH. 2009. Aspergillus flavus: An emerging non-fumigatus Aspergillus species of significance. Mycoses. 52:206–222.

64. Alastruey-Izquierdo A, Mellado E, Peláez T, Pemán J, Zapico S, Alvarez M, RodríguezTudela JL, Cuenca-Estrella M. 2013. Population-based survey of filamentous fungi and antifungal resistance in Spain (FILPOP study). Antimicrob Agents Chemother. 57:3380–3387.

65. Taccone FS, Van den Abeele A-M, Bulpa P, Misset B, Meersseman W, Cardoso T, Paiva J-A, Blasco-Navalpotro M, De Laere E, Dimopoulos G, Rello J, Vogelaers D, Blot SI. 2015. Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Crit Care. 19:7.

66. Vermeulen E, Maertens J, De Bel A, Nulens E, Boelens J, Surmont I, Mertens A, Boel A, Lagrou K. 2015. Nationwide surveillance of azole resistance in Aspergillus diseases. Antimicrob Agents Chemother. 59:4569–4576.

67. Pasqualotto AC. 2009. Differences in pathogenicity and clinical syndromes due to Aspergillus fumigatus and Aspergillus flavus. Med Mycol. 47 Suppl 1:S261–S270.

68. Krishnan-Natesan S, Chandrasekar PH, Alangaden GJ, Manavathu EK. 2008. Molecular characterisation of cyp51A and cyp51B genes coding for P450 14a-lanosterol demethylases A (CYP51Ap) and B (CYP51Bp) from voriconazole-resistant laboratory isolates of Aspergillus flavus. Int J Antimicrob Agents. 32:519–524.

69. Paul RA, Rudramurthy SM, Meis JF, Mouton JW, Chakrabarti A. 2015. A novel Y319H substitution in CYP51C associated with azole resistance in Aspergillus flavus. Antimicrob Agents Chemother. 59:6615–6619.

70. Natesan SK, Lamichchane AK, Swaminathan S, Wu W. 2013. Differential expression of ATP-binding cassette and/or major facilitator superfamily class efflux pumps contributes to voriconazole resistance in Aspergillus flavus. Diagn Microbiol Infect Dis. 76:458–463.

71. Camps SMT, Dutilh BE, Arendrup MC, Rijs AJMM, Snelders E, Huynen MA, Verweij PE, Melchers WJG. 2012. Discovery of a hapE mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing. PLoS One. 7(1): e50034.

72. Clinical and Laboratory Standards Institute. 2008. Reference method for broth microdilution antifungal susceptibility testing of yeasts; approved standard. CLSI document M27-A3, 3rd ed, vol 28. Clinical and Laboratory Standards Institute, Wayne, PA.

73. Escribano P, Recio S, Peláez T, González-Rivera M, Bouza E, Guinea J. 2012. In vitro acquisition of secondary azole resistance in Aspergillus fumigatus isolates after prolonged exposure to itraconazole: Presence of heteroresistant populations. Antimicrob Agents Chemother. 56:174–178.

74. Chang PK, Scharfenstein LL, Wei Q, Bhatnagar D. 2010. Development and refinement of a high-efficiency gene-targeting system for Aspergillus flavus. J Microbiol Methods. 81:240–246.

75. Osmani AH, Oakley BR and Osmani SA. 2006. Identification and analysis of essential Aspergillus nidulans genes using the heterokaryon rescue technique. Nature Protocols. 1: 2517 – 2526

76. Kuge S, Jones N. 1994. YAP1 dependent activation of TRX2 is essential for the response of Saccharomyces cerevisiae to oxidative stress by hydroperoxides. EMBO J. 13:655–664.

77. Alarco AM, Raymond M. 1999. The bZip transcription factor Cap1p is involved in multidrug resistance and oxidative stress response in Candida albicans. J Bacteriol. 181:700–708.

78. Lee J, Godon C, Spector D, Garin J, Toledano MB, Lagniel G, Labarre J. 1999. Yap1 and Skn7 control two specialized oxidative stress response regulons in yeast. J Biol Chem. 274:16040–16046.

79. Zhang X, Micheli M De, Coleman ST, Sanglard D, W. Scott Moye-Rowley. 2000. Analysis of the oxidative stress regulation of the Candida albicans transcription factor, Cap1p. Mol Cell Biol. 36:618–629.

80. Lessing F, Kniemeyer O, Wozniok I, Loeffler J, Kurzai O, Haertl A, Brakhage AA. 2007. The Aspergillus fumigatus transcriptional regulator AfYap1 represents the major regulator for defense against reactive oxygen intermediates but is dispensable for pathogenicity in an intranasal mouse infection model. Eukaryot Cell. 6:2290–2302.

81. Cuéllar-Cruz M, Briones-Martin-del-Campo M, Cañas-Villamar I, MontalvoArredondo J, Riego-Ruiz L, Castaño I, Peñas ADL. 2008. High resistance to oxidative stress in the fungal pathogen Candida glabrata is mediated by a single catalase, Cta1p, and is controlled by the transcription factors Yap1p, Skn7p, Msn2p, and Msn4p. Eukaryot Cell. 7:814–825.

82. Qiao J, Kontoyiannis DP, Calderone R, Li D, Ma Y, Wan Z, Li R, Liu W. 2008. Afyap1, encoding a bZip transcriptional factor of Aspergillus fumigatus, contributes to oxidative stress response but is not essential to the virulence of this pathogen in mice immunosuppressed by cyclophosphamide and triamcinolone. Med Mycol. 46:773–782.

83. Paul S, Doering TL, Moye-Rowley WS. 2015. Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance. Fungal Genet Biol. 74:1–9.

84. Merhej J, Thiebaut A, Blugeon C, Pouch J, Chaouche MEAA, Camadro J-M, Crom SL, Lelandais G, Devaux F. 2016. A network of paralogous stress response transcription factors in the human pathogen Candida glabrata. Front Microbiol. 7:645.

85. Kuge S, Jones N, Nomoto A. 1997. Regulation of yAP-1 nuclear localization in response to oxidative stress. EMBO J. 16:1710–1720.

86. Kuge S, Toda T, Iizuka N, Nomoto A. 1998. Crm1 (Xpol) dependent nuclear export of the budding yeast transcription factor yAP-1 is sensitive to oxidative stress. Genes to Cells. 3:521–532.

87. Yan C, Lee LH, Davis LI. 1998. Crm1p mediates regulated nuclear export of a yeast AP-1-like transcription factor. EMBO J. 17:7416–7429.

88. Coleman ST, Epping EA, Steggerda SM, Moye-rowley WS. 1999. Yap1p activates gene transcription in an oxidant-specific fashion. Mol Cell Biol. 19:8302–8313.

89. Delaunay A, Isnard AD, Toledano MB. 2000. H2O2 sensing through oxidation of the Yap1 transcription factor. EMBO J. 19:5157–5166.

90. Kuge S, Arita M, Murayama A, Maeta K, Izawa S, Inoue Y, Nomoto A. 2001. Regulation of the yeast Yap1p nuclear export signal is mediated by redox signal-induced reversible disulfide bond formation. Mol Cell Biol. 21:6139–6150.

91. Shekhova E, Kniemeyer O, Brakhage AA. 2017. Induction of mitochondrial reactive oxygen species production by against Aspergillus fumigatus. Antimicrob Agents Chemother. 61:1–14.

92. Mogavero S, Tavanti A, Senesi S, Rogers PD, Morschhäuser J. 2011. Differential requirement of the transcription factor Mcm1 for activation of the Candida albicans multidrug efflux pump MDR1 by its regulators Mrr1 and Cap1. Antimicrob Agents Chemother. 55:2061–2066.

93. Dunkel N, Blaß J, Rogers PD, Morschhäuser J. 2008. Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains. Mol Microbiol. 69:827–840.

94. Alarco AM, Balan I, Talibi D, Mainville N, Raymond M. 1997. Ap1-mediated multidrug resistance in Saccharomyces cerevisiae requires FLR1 encoding a transporter of the major facilitator superfamily. J Biol Chem. 272:19304–19313.

95. Chen KH, Miyazaki T, Tsai H, Bennett JE. 2007. The bZip transcription factor Cgap1p is involved in multidrug resistance and required for activation of multidrug transporter gene CgFLR1 in Candida glabrata. Gene. 386:63–72.

96. Abruzzo GK, Gill CJ., Flattery AM, Kong L, Leighton C, Smith JG, Pikounis VB., Bartizal K, Rosen H. 2000. Efficacy of the echinocandin caspofungin against disseminated aspergillosis and candidiasis in cyclophosphamide-induced immunosuppressed mice. Antimicrob Agents Chemother. 44:2310–2318.

97. Clemons KV, Stevens DA. 1998. Comparison of Fungizone, Amphotec, AmBisome, and Abelcet for treatment of systemic murine cryptococcosis. Antimicrob Agents Chemother. 42:899–902.

98. Bowman JC, Abruzzo GK, Anderson JW, Flattery, AM, Gill CJ, Pikounis VB, Schmatz DM, Liberator A, Douglas CM. 2001. Quantitative PCR assay to measure Aspergillus fumigatus burden in a murine model of disseminated aspergillosis: Demonstration of efficacy of caspofungin acetate. Antimicrob Agents Chemother. 45:3474–3481.

99. Lepak AJ, Marchillo K, VanHecker J, Andes DR. 2013. Impact of in vivo triazole and echinocandin combination therapy for invasive pulmonary aspergillosis: Enhanced efficacy against Cyp51 mutant isolates. Antimicrob Agents Chemother. 57:5438–5447.

100.Lepak AJ, Marchillo K, VanHecker J, Andes DR. 2013. Posaconazole pharmacodynamic target determination against wild-type and Cyp51 mutant isolates of Aspergillus fumigatus in an in vivo model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 57:579–585.

101.Lepak AJ, Marchillo K, VanHecker J, Andes DR. 2013. Isavuconazole (BAL4815) pharmacodynamic target determination in an in vivo murine model of invasive pulmonary aspergillosis against wild-type and cyp51 mutant isolates of Aspergillus fumigatus. Antimicrob Agents Chemother. 57:6284–6289

102.Herrera ML, Vallor AC, Gelfond JA, Patterson TF, Wickes BL. 2009. Strain-dependent variation in 18S ribosomal DNA copy numbers in aspergillus fumigatus. J Clin Microbiol. 47:1325–1332.

103.Mercier T, Guldentops E, Lagrou K, Maertens J. 2018. Galactomannan, a surrogate marker for outcome in invasive aspergillosis: Finally coming of age. Front Microbiol. 9:661.

104.Gebremariam T, Alkhazraji S, Gu Y, Singh S, Alqarihi A, Shaw KJ., Ibrahim AS. 2020. Galactomannan is a biomarker of fosmanogepix (APX001) efficacy in treating experimental invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 64(1): e01966-19

105.Hope WW, McEntee L, Livermore J, Whalley S, Johnson A, Farrington N, Kolamunnage-Dona R, Schwartz J, Kennedy A, Law D, Birch M, Rex JH. 2017. Pharmacodynamics of the orotomides against Aspergillus fumigatus: New opportunities for treatment of multidrug-resistant fungal disease. mBio. 8:e01157-17.

106.Kimura G, Nakaoki T, Colley T, Rapeport G, Strong P, Ito K, Kizawa Y. 2017. In vivo biomarker analysis of the effects of intranasally dosed PC945, a novel antifungal triazole, on Aspergillus fumigatus infection in immunocompromised mice. Antimicrob Agents Chemother. 61(9):e00124-17

107.Hagiwara D, Takahashi H, Watanabe A, Takahashi-Nakaguchi A, Kawamoto S, Kamei K, Gonoi T. 2014. Whole-genome comparison of Aspergillus fumigatus strains serially isolated from patients with aspergillosis. J Clin Microbiol. 52:4202–4209.

108.Geißel B, Loiko V, Klugherz I, Zhu Z, Wagener N, Kurzai O, van den Hondel CAMJJ, Wagener J. 2018. Azole-induced cell wall carbohydrate patches kill Aspergillus fumigatus. Nat Commun. 9:3098

109.Petraitiene R, Petraitis V, Groll AH, Sein T, Schaufele RL, Francesconi A, Bacher J, Avila NA, Walsh TJ. 2002. Antifungal efficacy of caspofungin (MK-0991) in experimental pulmonary aspergillosis in persistently neutropenic rabbits: Pharmacokinetics, drug disposition, and relationship to galactomannan antigenemia. Antimicrob Agents Chemother. 46:12–23.

110.Oliver JD, Sibley GEM, Beckmann N, Dobb KS, Slater MJ, McEntee L, du Pré S, Livermore J, Bromley MJ, Wiederhold NP, Hope WW, Kennedy AJ, Law D, and Birch M. 2016. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci. 113 (45) 12809-12814

111.Buil JB, Rijs AJMM, Meis JF, Birch M, Law D, Melchers WJG, Verweij PE. 2017. In vitro activity of the novel antifungal compound F901318 against difficult-to-treat Aspergillus isolates. J Antimicrob Chemother. 72(9):2548–2552.

112.Gebremariam T, Alkhazraji S, Alqarihi A, Jeon HH, Gu Y, Kapoor M, Shaw KJ, and Ibrahim AS. 2019. APX001 is effective in the treatment of murine invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 63(2):e01713-18.

113.Pfaller MA, Duncanson F, Messer SA. Moet GJ, Jones RN and Castanheira M. 2011. In vitro activity of a novel broad-spectrum antifungal, E1210, tested against Aspergillus spp. determined by CLSI and EUCAST broth microdilution methods. Antimicrob Agents Chemother. 55(11): 5155–5158.

114.Kato I, Ukai Y, Kondo N, Nozu K, Kimura C, Hashimoto K, Mizusawa E, Maki H, Naito A and Kawai M. 2021. Identification of thiazoyl guanidine derivatives as novel antifungal agents inhibiting ergosterol biosynthesis for treatment of invasive fungal infections. J Med Chem. 64(14), 10482-10496.

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文

一発検索!

この論文の関連論文を見る