Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml
Synlett 2016; 27(03): 337-354
DOI: 10.1055/s-0035-1560800
DOI: 10.1055/s-0035-1560800
account
Our Path to Less Toxic Amphotericins
Further Information
Publication History
Received: 21 July 2015
Accepted after revision: 06 October 2015
Publication Date:
09 December 2015 (online)
Abstract
We launched our research program with the search for small molecule replacements for missing proteins that underlie currently incurable human diseases. This pursuit drew us to amphotericin B, a remarkable natural product that is the archetype for ion-channel-forming small molecules. We quickly realized, however, that there was a second very important reason to study this natural product, as it represents the most powerful, broad-spectrum, and resistance-evasive treatment for invasive fungal infections, which still kill more than 1.5 million people each year – more than malaria or tuberculosis. The problem with amphotericin B is that it is highly toxic to humans, which limits the dose that can be administered. Through an extensive series of synthesis-enabled studies, we came to understand that, in contrast to the long-standing mechanistic model, amphotericin B kills yeast by simply binding ergosterol – channel formation is not required. This allowed us to focus squarely on the actionable problem of selectively binding ergosterol over cholesterol en route to an improved therapeutic index. This journey has yielded new types of amphotericin derivatives that bind ergosterol but not (detectably) cholesterol, and kill yeast but are substantially less toxic than amphotericin B in vitro and in vivo. This advanced mechanistic understanding has also brightened the prospect of developing small molecules that replace missing protein ion channels, thereby operating as prostheses on the molecular scale.
-
References
- 1 Ellis D. J. Antimicrob. Chemother. 2002; 49: 7
- 2 Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Sci. Transl. Med. 2012; 4: 165rv13
- 3 Katzung BG. Basic and Clinical Pharmacology . Seventh Edition McGraw-Hill Education; New York: 1998: 780
- 4 Chen WC, Chou D, Feingold DS. Antimicrob. Agents Chemother. 1978; 13: 914
- 5a Gold W, Stout HA, Pagano JF, Donovick R. Antiobiot. Annu. 1955; 3: 579
- 5b Vandeputte J, Wachtel JL, Stiller ET. Antibiot. Annu. 1955; 3: 587
- 5c Sternberg TH, Wright ET, Oura M. Antibiot. Annu. 1955; 3: 566
- 5d Steinberg BA, Jambor WP, Suydom LO. Antiobiot. Annu. 1955; 3: 574
- 6 Akaike N, Harata N. Jpn. J. Physiol. 1994; 44: 433
- 7a Halde C, Newcomer VD, Wright ET, Sternberg TH. J. Invest. Dermatol. 1957; 28: 217
- 7b Procknow JJ, Loosli CG. Arch. Intern. Med. 1958; 101: 765
- 8a Gottlieb D, Carter HE, Sloneker JH, Ammann A. Science 1958; 128: 361
- 8b Gottlieb D, Carter HE, Gaudy E. Bacteriol. Proc. 1959; 114
- 9a Palacios DS, Anderson TM, Burke MD. J. Am. Chem. Soc. 2007; 129: 13804
- 9b Palacios DS, Dailey I, Siebert DM, Wilcock BC, Burke MD. Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 6733
- 9c Gray KC, Palacios DS, Dailey I, Endo MM, Uno BE, Wilcock BC, Burke MD. Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 2234
- 9d Anderson TM, Clay MC, Cioffi AG, Diaz KA, Hisao GS, Tuttle MD, Nieuwkoop AJ, Comellas G, Wang S, Uno BE, Wildeman EL, Maryum N, Gonen T, Rienstra CM, Burke MD. Nat. Chem. Biol. 2014; 10: 400
- 10a Kinsky SC. Biochem. Biophys. Res. Commun. 1961; 4: 353
- 10b Kinsky SC. J. Bacteriol. 1961; 82: 889
- 11 Andreoli TE, Monahan M. J. Gen. Physiol. 1968; 52: 300
- 12 Cass A, Finkelstein A, Krespi V. J. Gen. Physiol. 1970; 56: 100
- 13 Ermishkin LN, Kasumov KM, Potzeluyev VM. Nature 1976; 262: 698
- 15 Finkelstein A, Holz R In Membranes. Lipid Bilayers and Antibiotics . Vol. 2. Eisenman G. Marcel Dekker Inc; New York: 1973: 377
- 16 de Kruijff B, Demel RA. BBA-Biomembranes 1974; 339: 57
- 17a Khutorsky VE. BBA-Biomembranes 1992; 1108: 123
- 17b Baginski M, Resat H, MacCammon JA. Mol. Pharmacol. 1997; 52: 560
- 17c Baginski M, Resat H, Borowski E. BBA-Biomembranes 2002; 1567: 63
- 18a Chéron M, Cybulska B, Mazerski J, Grzybowska J, Czerwiński A, Borowski E. Biochem. Pharmacol. 1988; 37: 827
- 18b Hervé M, Debouzy JC, Borowski E, Cybulska B, Gary-Bobo CM. Biochim. Biophys. Acta 1989; 980: 261
- 18c Mazerski J, Bolard J, Borowski E. Biochim. Biophys. Acta 1995; 1236: 170
- 18d Matsumori N, Eiraku N, Matsuoka S, Oishi T, Murata M, Aoki T, Ide T. Chem. Biol. 2004; 11: 673
- 18e Kasai Y, Matsumori N, Umegawa Y, Matsuoka S, Ueno H, Ikeuchi H, Oishi T, Murata M. Chem. Eur. J. 2008; 14: 1178
- 18f Matsumori N, Sawada Y, Murata M. J. Am. Chem. Soc. 2005; 127: 10667
- 18g Neumann A, Czub J, Baginski M. J. Phys. Chem. B 2009; 113: 15875
- 18h Neumann A, Baginski M, Czub J. J. Am. Chem. Soc. 2010; 132: 18266
- 19a Matsumori N, Tahara K, Yamamoto H, Morooka A, Doi M, Oishi T, Murata M. J. Am. Chem. Soc. 2009; 131: 11855
- 19b Matsuoka S, Murata M. Biochim. Biophys. Acta 2002; 1564: 429
- 19c Kasai Y, Matsumori N, Umegawa Y, Matsuoka S, Ueno H, Ikeuchi H, Oishi T, Murata M. Chem. Eur. J. 2008; 14: 1178
- 20a HsuChen C.-C, Feingold DS. Biochem. Biophys. Res. Commun. 1973; 51: 972
- 20b HsuChen C.-C, Feingold DS. Antimicrob. Agents Chemother. 1973; 4: 309
- 20c Zumbuehl A, Stano P, Heer D, Walde P, Carreira EM. Org. Lett. 2004; 6: 3683
- 21 Umegawa Y, Matsumori N, Oishi T, Murata M. Tetrahedron Lett. 2007; 48: 3393
- 22 Matsuoka S, Matsumori N, Murata M. Org. Biomol. Chem. 2003; 1: 3882
- 23a Mathias JP, Simanek EE, Whitesides GM. J. Am. Chem. Soc. 1994; 116: 4326
- 23b Görbitz CH, Etter MC. J. Am. Chem. Soc. 1992; 114: 627
- 24 Bolard J. Biochim. Biophys. Acta 1986; 864: 257
- 25 Volmer AA, Szpilman AM, Carreira EM. Nat. Prod. Rep. 2010; 27: 1329
- 26 Milhaud J, Ponsinet V, Takashi M, Michels B. Biochim. Biophys. Acta 2002; 1558: 95
- 27a Murata M, Kasai Y, Umegawa Y, Matsushita N, Tsuchikawa H, Matsumori N, Oishi T. Pure Appl. Chem. 2009; 81: 1123
- 27b Matsumori N, Sawada Y, Murata M. J. Am. Chem. Soc. 2006; 128: 11977
- 27c Matsuoka S, Ikeuchi H, Umegawa Y, Matsumori N, Murata M. Bioorg. Med. Chem. 2006; 14: 6608
- 27d Umegawa Y, Nakagawa Y, Tahara K, Tsuchikawa H, Matsumori N, Oishi T, Murata M. Biochemistry 2012; 51: 83
- 28 Verkleij AJ, de Kruuff B, Gerritsen WF, Demel RA, van Deenen LL. M, Ververgaert PH. J. Biochim. Biophys. Acta 1973; 291: 577
- 29 Mouri R, Konoki K, Matsumori N, Oishi T, Murata M. Biochemistry 2008; 47: 7807
- 30 Ernst C, Grange J, Rinnert H, Dupont G, Lematre J. Biopolymers 1981; 20: 1575
- 31 Paquet MJ, Fournier I, Barwicz J, Tancréde P, Auger M. Chem. Phys. Lipids 2002; 119: 1
- 32 Hoogevest PV, de Kruijff B. Biochim. Biophys. Acta 1978; 511: 397
- 33a Baran M, Mazerski J. Biophys. Chem. 2002; 95: 125
- 33b Czub J, Neumann A, Borowski E, Baginski M. Biophys. Chem. 2009; 141: 105
- 34a Trauger JW, Kohli RM, Mootz HD, Marahiel MA, Walsh CT. Nature 2000; 407: 215
- 34b Keating TA, Ehmann DE, Kohli RM, Marshall CG, Trauger JW, Walsh CT. ChemBioChem 2001; 2: 99
- 34c Kohli RM, Trauger JW, Schwarzer D, Marahiel MA, Walsh CT. Biochemistry 2001; 40: 7099
- 34d Trauger JW, Kohli RM, Walsh CT. Biochemistry 2001; 40: 7092
- 34e Kohli RM, Takagi J, Walsh CT. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 1247
- 34f Bruner SD, Weber T, Kohli RM, Schwarzer D, Marahiel MA, Walsh CT, Stubbs MT. Structure 2002; 10: 301
- 34g Luo LS, Kohli RM, Onishi M, Linne U, Marahiel MA, Walsh CT. Biochemistry 2002; 41: 9184
- 34h Kohli RM, Walsh CT, Burkart MD. Nature 2002; 418: 658
- 34i Tseng CC, Bruner SD, Kohli RM, Marahiel MA, Walsh CT, Sieber SA. Biochemistry 2002; 41: 13350
- 34j Kohli RM, Walsh CT. Chem. Commun. 2003; 3: 297
- 34k Kohli RM, Burke MD, Tao JH, Walsh CT. J. Am. Chem. Soc. 2003; 125: 7160
- 34l Yeh E, Kohli RM, Bruner SD, Walsh CT. ChemBioChem 2004; 5: 1290
- 34m Yeh E, Lin HN, Clugston SL, Kohli RM, Walsh CT. Chem. Biol. 2004; 11: 1573
- 35a Nicolaou KC, Chakraborty TK, Ogawa Y, Daines RA, Simpkins NS, Furst GT. J. Am. Chem. Soc. 1988; 110: 4660
- 35b Kennedy RM, Abiko A, Masamune S. Tetrahedron Lett. 1988; 29: 447
- 36 te Welscher YM, ten Napel HH, Masiá Balagué M, Souza CM, Riezman H, de Kruijff B, Breukink E. J. Biol. Chem. 2008; 283: 6393
- 37a Urbina JA, Pekerar S, Le HB, Patterson J, Montez B, Oldfield E. Biochim. Biophys. Acta 1995; 1238: 163
- 37b Henriksen J. Biophys. J. 2006; 90: 1639
- 37c Hsueh YW, Chen MT, Patty PJ, Code C, Cheng J, Frisken BJ, Zuckermann M, Thewalt J. Biophys. J. 2007; 92: 1606
- 38 te Welscher YM, Jones L, van Leeuwen MR, Dijksterhuis J, de Kruijff B, Eitzen G, Breukink E. Antimicrob. Agents Chemother. 2010; 54: 2618
- 39a Kato M, Wickner W. EMBO J. 2001; 20: 4035
- 39b Heese-Peck A, Pichler H, Zanolari B, Watanabe R, Daum G, Riezman H. Mol. Cell. Biol. 2002; 13: 2664
- 39c Jin H, McCaffery JM, Grote E. J. Cell Biol. 2008; 180: 813
- 39d Klose C, Ejsing CS, García-Sáez AJ, Kaiser HJ, Sampaio JL, Surma MA, Shevchenko A, Schwille P, Simons K. J. Biol. Chem. 2010; 285: 30224
- 39e Zhang YQ. PLoS Pathog. 2010; 6: e10000939
- 40 Vincent BM, Lancaster AK, Scherz-Shouval R, Whitesell L, Lindquist S. PLoS Biol. 2013; 11: e1001692
- 41 Merrifield RB. Science 1965; 150: 178
- 42 Caruthers MH. Science 1985; 230: 281
- 43 Plante OJ, Palmacci ER, Seeberger PH. Science 2001; 291: 1523
- 44a Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
- 44b Negishi E.-I In Handbook of Organopalladium Chemistry for Organic Synthesis. Vol. 1. Wiley; New York: 2002
- 45 A similar approach with a different mechanism of blocking boronic acid reactivity was pursued contemporaneously by the Suginome group at Kyoto University. Noguchi H, Hojo K, Suginome M. J. Am. Chem. Soc. 2007; 129: 758
- 46a Carrow BP, Hartwig JF. J. Am. Chem. Soc. 2011; 133: 2116
- 46b Amatore C, Jutand A, Le Duc G. Chem. Eur. J. 2011; 17: 2492
- 46c Matos K, Soderquist J. J. Org. Chem. 1998; 63: 461
- 46d Miyaura N. J. Organomet. Chem. 2002; 653: 54
- 47a Mancilla T, Contreras R. J. Organomet. Chem. 1986; 307: 1
- 47b Mancilla T, Zamudio-Rivera LS, Beltrán HI, Santillan R, Farfán N. ARKIVOC 2005; (vi): 366
- 47c Contreras R, García C, Mancilla T, Wrackmeyer B. J. Organomet. Chem. 1983; 246: 213
- 48 Gillis EP, Burke MD. J. Am. Chem. Soc. 2007; 129: 6716
- 49 Gillis EP, Burke MD. J. Am. Chem. Soc. 2008; 130: 14084
- 50a Knapp DM, Gillis EP, Burke MD. J. Am. Chem. Soc. 2009; 131: 6961
- 50b Lennox AJ. J, Lloyd-Jones GC. Isr. J. Chem. 2010; 50: 664
- 51 Li J, Burke MD. J. Am. Chem. Soc. 2011; 133: 13774
- 52 Li J, Ballmer SG, Gillis EP, Fujii S, Schmidt MJ, Palazzolo AM. E, Lehmann JW, Morehouse GF, Burke MD. Science 2015; 347: 1221
- 53 Lee SJ, Gray KC, Paek JS, Burke MD. J. Am. Chem. Soc. 2008; 130: 466
- 54 Woerly EM, Cherney AH, Davis EK, Burke MD. J. Am. Chem. Soc. 2010; 132: 6941
- 55 Fujii S, Chang SY, Burke MD. Angew. Chem. Int. Ed. 2011; 50: 7862
- 56 Woerly EM, Roy J, Burke MD. Nat. Chem. 2014; 6: 484
- 57 Lee SJ, Anderson TM, Burke MD. Angew. Chem. Int. Ed. 2010; 49: 8860
- 58 See: http://www.istem.illinois.edu/news/burke.htm.
- 59a Szpilman AM, Manthorpe JM, Carreira EM. Angew. Chem. Int. Ed. 2008; 47: 4339
- 59b Szpilman AM, Cereghetti DM, Manthorpe JM, Wurtz NR, Carreira EM. Chem. - Eur. J. 2009; 15: 7117
- 60a Solomon I. Phys. Rev. 1955; 99: 559
- 60b Nadaud PS, Helmus JJ, Hofer N, Jaroniec CP. J. Am. Chem. Soc. 2007; 129: 7502
- 60c Sankaram MB, Thompson TE. Proc. Natl. Acad. Sci. U.S.A. 1991; 88: 8686
- 61 Haas AA. Methods Cell Sci. 1995; 17: 283
- 62 Croatt MP, Carreira EM. Org. Lett. 2011; 13: 1390
- 63 Wilcock BC, Endo MM, Uno BE, Burke MD. J. Am. Chem. Soc. 2013; 135: 8488
- 64a Duggan KC, Hermanson DJ, Musee J, Prusakiewicz JJ, Scheib JL, Carter BD, Banerjee S, Oates JA, Mernett LJ. Nat. Chem. Biol. 2011; 7: 803
- 64b Neant-Fery M, Garcia-Ordonez RD, Logan TP, Selkoe DJ, Li L, Reinstatler L, Leissring MA. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 9582
- 64c Knight ZA, Shokat KM. Chem. Biol. 2005; 12: 621
- 64d Koike K, Oleschuk CJ, Haimeur A, Olsen SL, Deeley RG, Cole SP. C. J. Biol. Chem. 2002; 277: 49495
- 64e Changeux JP, Edelstein SJ. Neuron 1998; 21: 959
- 65 Fowler BS, Laemmerhold KM, Miller SJ. J. Am. Chem. Soc. 2012; 134: 9755
- 66a Ganis P, Avitabile G, Mechlinski W, Schaffner CP. J. Am. Chem. Soc. 1971; 93: 4560
- 66b Jarzembska KN, Kaminski D, Hoser AA, Malinska M, Senczyna B, Wozniak K, Gagos M. Cryst. Growth Des. 2012; 12: 2336
- 67a Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, Paterson DL. Lancet Infect. Dis. 2006; 6: 589
- 67b Cortes JE, Kim D.-W, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H. New Engl. J. Med. 2013; 369: 1783
- 68 Davis SA, Vincent BM, Endo MM, Whitesell L, Marchillo K, Andes DR, Lindquist S, Burke MD. Nat. Chem. Biol. 2015; 11: 481
- 69a Bonner DP, Mechlinski W, Schaffner CP. J. Antibiot. 1972; 25: 261
- 69b Keim GR, Sibley PL, Yoon YH, Kulesza JS, Zaida IH, Miller MM, Poutsiaka JW. Antimicrob. Agents Chemother. 1976; 10: 687
- 70 Tevyashova AN, Olsufyeva EN, Solovieva SE, Printsevskaya SS, Reznikova MI, Trenin AS, Galatenko OA, Treshalin ID, Pereverzeva ER, Mirchink EP, Isakova EB, Zotchev SB, Preobrazhenskaya MN. Antimicrob. Agents Chemother. 2013; 57: 3815
- 71 Paquet V, Volmer AA, Carreira EM. Chemistry 2008; 14: 2465
- 72a Pfaller M, Neofytos D, Diekema D, Azie N, Meier-Kriesche HU, Quan SP, Horn D. Diagn. Microbiol. Infec. Dis. 2012; 74: 323
- 72b Cruz MC, Del Poeta M, Wang P, Wengeer R, Zenke G, Quesniaux VF, Movva NR, Perfect JR, Cardenas ME, Heitman J. Antimicrob. Agents Chemother. 2000; 44: 143
- 72c Lepak AJ, Marchillo K, Vanhecker J, Andes DR. Antimicrob. Agents Chemother. 2013; 57: 579
- 73 Ellis JK, Athersuch TJ, Cavill R, Radford R, Slattery C, Jennings P, McMorrow T, Ryan MP, Ebbeis TM, Keun HC. Mol. Biosyst. 2011; 7: 247
- 74 Andes D, Stamsted T, Conklin R. Antimicrob. Agents Chemother. 2001; 45: 922
- 75 Cioffi AG, Hou J, Grillo AG, Diaz KA, Burke MD. J. Am. Chem. Soc. 2015; 137: 10096
The methyl ester of C35deOAmB was synthesized and studied by Carreira and coworkers, and they offered a different interpretation of their results.