Abstract
The first echinocandin-type antimycotic (echinocandin B) was discovered in the 1970s. It was followed by the isolation of more than 20 natural echinocandins. These cyclic lipo-hexapeptides are biosynthesized on non-ribosomal peptide synthase complexes by different ascomycota fungi. They have a unique mechanism of action; as non-competitive inhibitors of β-1,3-glucan synthase complex they target the fungal cell wall. Results of the structure–activity relationship experiments let us develop semisynthetic derivatives with improved properties. Three cyclic lipohiexapeptides (caspofungin, micafungin and anidulafungin) are currently approved for use in clinics. As they show good fungicidal (Candida spp.) or fungistatic (Aspergillus spp.) activity against the most important human pathogenic fungi including azole-resistant strains, they are an important addition to the antifungal armamentarium. Some evidence of acquired resistance against echinocandins has been detected among Candida glabrata strains in recent years, which enhanced the importance of data collected on the mechanism of acquired resistance developing against the echinocandins. In this review, we show the structural diversity of natural echinocandins, and we summarize the emerging data on their mode of action, biosynthesis and industrial production. Their clinical significance as well as the mechanism of natural and acquired resistance is also discussed.
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Adefarati AA, Giacobbe RA, Hensens OD, Tkacz JS (1991) Biosynthesis of L-671,329, an echinocandin-type antibiotic produced by Zalerion arboricola: origins of some of the unusual amino acids and the dimethylmyristic acid side-chain. J Am Chem Soc 113:3542–3545
Adefarati AA, Hensens OD, Jones ET, Tkacz JS (1992) Pneumocandins from Zalerion arboricola V. Glutamic acid- and leucinederived amino acids in pneumocandin Ao (l-671,329) and distinct origins of the substituted proline residues in pneumocandins Ao and Bo. J Antibiot 45:1953–1957
Arendrup MC, Perkhofer S, Howard SJ, Garcia-Effron G, Vishukumar A, Perlin D, Lass-Florl C (2008) Establishing in vitro–in vivo correlations for Aspergillus fumigatus: the challenge of azoles versus echinocandins. Antimicrob Agents Chemother 52:3504–3511
Arikan S, Lozano-Chiu M, Paetznick V, Rex JH (2001) In vitro susceptibility testing methods for caspofungin against Aspergillus and Fusarium isolates. Antimicrob Agents Chemother 45:327–330
Aszodi J, Fauveau P, Melon-Manguer D, Ehlersb E, Schioa L (2002) Synthesis of new echinocandin derivatives via a diol-keto transposition. Tetrahedron Lett 43:2953–2956
Bachmann SP, VandeWalle K, Ramage G, Patterson TF, Wickes BL, Graybill JR, López-Ribot JL (2002a) In vitro activity of caspofungin against Candida albicans biofilms. Antimicrob Agents Chemother 46:3591–3596
Bachmann SP, Patterson TF, Lopez-Ribot JL (2002b) In vitro activity of caspofungin (MK-0991) against Candida albicans clinical isolates displaying different mechanisms of azole resistance. J Clin Microbiol 40:2228–2230
Bacic A, Fincher GB, Stone BA (2009) Chemistry, biochemistry, and biology of 1–3 beta glucans and related polysaccharides. Academic Press, Amsterdam
Bal AM (2010) The echinocandins: three useful choices or three too many? Int J Antimicrob Agents 35:13–18
Balashov SV, Park S, Perlin DS (2006) Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother 50:2058–2063
Balkovec JM, Black RM, Abruzzo GK, Bartizal K, Dreikorn S, Nollstadt K (1993) Pneumocandin antifungal lipopeptides. The phenolic hydroxyl is required for 1,3- β-D-glucan synthesis inhibition. Bioorg Med Chem Lett 3:2039–2042
Bayegan S, Szilágyi J, Kemény-Beke Á, Földi R, Kardos G, Gesztelyi R, Juhasz B, Adnan A, Majoros L (2011) Efficacy of a single 6 mg/kg versus two 3 mg/kg caspofungin doses for treatment of disseminated candidiasis caused by Candida albicans in a neutropenic mouse model. J Chemother 23:107–109
Ben-Ami R, Garcia-Effron G, Lewis RE, Gamarra S, Leventakos K, Perlin DS, Kontoyiannis DP (2011) Fitness and virulence costs of Candida albicans fks1 hot spot mutations associated with echinocandin resistance. J Infect Dis 204:626–635
Benz F, Knüsel F, Nüesch J, Treichler H, Voser W, Nyfeler R, Keller-Schierlein W (1974) Stoffwechselprodukte von Mikroorganismen 143. Mitteilung. Echinocandin B, ein neuartiges Polypeptid-Antibioticum aus Aspergillus nidulans var. echinulatus: Isolierung und Bausteine. Helv Chim Acta 57:2459–2477
Betts RF, Nucci M, Talwar D, Gareca M, Queiroz-Telles F, Bedimo RJ, Herbrecht R, Ruiz-Palacios G, Young JA, Baddley JW, Strohmaier KM, Tucker KA, Taylor AF, Kartsonis NA; Caspofungin High-Dose Study Group (2009) A Multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis 48:1676–1684
Bills GF, Platas G, Peláez F, Masurekar P (1999) Reclassification of a pneumocandin-producing anamorph, Glarea lozoyensis gen. et sp. nov., previously identified as Zalerion arboricola. Mycol Res 103:179–192
Boeck LD, Kastner RE (1981) Method of producing the A-30912 antibiotics. US Pat 4:288–549
Bouffard FA, Zambias RA, Dropinski JF, Balkovec JM, Hammond ML, Abruzzo GK, Bartizal KF, Marrinan JA, Kurtz MB, McFadden DC, Nollstadt KH, Powles MA, Schmatz DM (1994) Synthesis and antifungal activity of novel cationic pneumocandin B0 derivatives. J Med Chem 37:222–225
Bowman JC, Hicks PS, Kurtz MB, Rosen H, Schmatz DM, Liberator PA, Douglas CM (2002) The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob Agents Chemother 46:3001–3012
Bryskier A (2005) Peptide antibiotics. In: Bryskier A (ed) Antimicrobial agents: Antibacterials and antifungals. ASM Press, Washington, pp 826–879
Cacho RA, Jiang W, Chooi YH, Walsh CT, Tang Y (2012) Identification and characterization of the echinocandin B biosynthetic gene cluster from Emericella rugulosa NRRL 11440. J Am Chem Soc 134:16781–16790
Calvo E, Pastor FJ, Mayayo E, Guarro J (2011) Efficacy of anidulafungin against Aspergillus niger in vitro and in vivo. Int J Antimicrob Agents 38:360–363
Calvo E, Pastor FJ, Salas V, Mayayo E, Guarro J (2012) Combined therapy of voriconazole and anidulafungin in murine infections by Aspergillus flavus. Mycopathologia 173:251–257
Cassone A, Mason R, Kerridge D (1981) Lysis of growing yeast-form cells of Candida albicans by echinocandin: a cytological study. Sabouraudia 19:97–110
Chamilos G, Lewis RE, Albert N, Kontoyiannis DP (2007) Paradoxical effect of echinocandins across Candida species in vitro: evidence for echinocandin-specific and Candida species-related differences. Antimicrob Agents Chemother 51:2257–2259
Chandrasekar PH, Sobel JD (2006) Micafungin: a new echinocandin. Clin Infect Dis 42:1171–1178
Chen SC, Slavin MA, Sorrell TC (2011) Echinocandin antifungal drugs in fungal infections: a comparison. Drugs 71:11–41
Clancy CJ, Huang H, Cheng SH, Derendorf H, Nguyen MH (2006) Characterizing the effects of caspofungin on Candida albicans, Candida parapsilosis, and Candida glabrata isolates by simultaneous time-kill and postantifungal-effect experiments. Antimicrob Agents Chemother 50:2569–2572
Clemons KV, Espiritu M, Parmar R, Stevens DA (2006) Assessment of paradoxical effect of caspofungin in therapy of candidiasis. Antimicrob Agents Chemother 50:1293–1297
Connors N, Pollard D (2004) Pneumocandin B0 production by fermentation of the fungus Glarea lozoyensis. In: Zhiqiang A (ed) Handbook of Industrial Mycology. Marcel Dekker, New York, pp 515–538
Connors N, Petersen L, Hughes R, Saini K, Olewinski R, Salmon P (2000) Residual fructose and osmolality affect the levels of pneumocandins B0 and C0 produced by Glarea lozoyensis. Appl Microbiol Biotechnol 54:814–818
Cushion MT, Collins MS (2011) Susceptibility of Pneumocystis to echinocandins in suspension and biofilm cultures. Antimicrob Agents Chemother 55:4513–4518
De Rosa FG, Garazzino S, Pasero D, Di Perri G, Ranieri VM (2009) Invasive candidiasis and candidemia: new guidelines. Minerva Anestesiol 75:453–458
Debono M, Gordee RS (1994) Antibiotics that inhibit fungal cell wall development. Annu Rev Microbiol 48:471–497
Debono M, Abbott BJ, Turner JR, Howard LC, Gordee RS, Hunt AS, Barnhart M, Molloy RM, Willard KE, Fukuda D, Butler TF, Zeckner DJ (1988) Synthesis and evaluation of LY121019, a member of a series of semisynthetic analogues of the antifungal lipopeptide echinocandin B. Ann N Y Acad Sci 544:152–167
Debono M, Abbott BJ, Fukuda DS, Barnhart M, Willard KE, Molloy RM, Michel KH, Turner JR, Butler TF, Hunt AH (1989) Synthesis of new analogs of echinocandin B by enzymatic deacylation and chemical reacylation of the echinocandin B peptide: synthesis of the antifungal agent cilofungin (LY121019). J Antibiot 42:389–397
Debono M, Turner WW, LaGrandeur L, Burkhardt FJ, Nissen JS, Nichols KK, Rodriguez MJ, Zweifel MJ, Zeckner DJ, Gordee RS, Tang J, Parr TR (1995) Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure–activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem 38:3271–3281
Dichtl K, Helmschrott C, Dirr F, Wagener J (2012) Deciphering cell wall integrity signalling in Aspergillus fumigatus: identification and functional characterization of cell wall stress sensors and relevant Rho GTPases. Mol Microbiol 83:506–519
DiDone L, Oga D, Krysan DJ (2011) A novel assay of biofilm antifungal activity reveals that amphotericin B and caspofungin lyse Candida albicans cells in biofilms. Yeast 28:561–568
Douglas CM (2006) Understanding the microbiology of the Aspergillus cell wall and the efficacy of caspofungin. Med Mycol 44:S95–S99
Douglas CM, D’Ippolito JA, Shei GJ, Meinz M, Onishi J, Marrinan JA, Li W, Abruzzo GK, Flattery A, Bartizal K, Mitchell A, Kurtz MB (1997) Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother 41:2471–2479
Drouhet E, Dupont B, Improvisi L, Lesourd M, Prevost MC (1990) Activity of cilofungin (LY 121019), a new lipopeptide antibiotic, on the cell wall and cytoplasmic membrane of Candida albicans. Structural modifications in scanning and transmission electron microscopy. J Med Vet Mycol 28:425–436
Espinel-Ingroff A (2003) In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature. Rev Iberoam Micol 20:121–136
Földi R, Szilágyi J, Kardos G, Berényi R, Kovács R, Majoros L (2012) Effect of 50 % human serum on the killing activity of micafungin against eight Candida species using time-kill methodology. Diagn Microbiol Infect Dis 73:338–342
Fortwendel JR, Juvvadi PR, Perfect BZ, Rogg LE, Perfect JR, Steinbach WJ (2010) Transcriptional regulation of chitin synthases by calcineurin controls paradoxical growth of Aspergillus fumigatus in response to caspofungin. Antimicrob Agents Chemother 54:1555–1563
Fujie A (2007) Discovery of micafungin (FK463): a novel antifungal drug derived from a natural product lead. Pure Appl Chem 79:603–614
Fujie A, Iwamoto T, Sato B, Muramatsu H, Kasahara C, Furuta T, Hori Y, Hino M, Hashimoto S (2001) FR131535, a novel water-soluble echinocandin-like lipopeptide: synthesis and biological properties. Bioorg Med Chem Lett 11:399–402
Ganesan LT, Manavathu EK, Cutright JL, Alangaden GJ, Chandrasekar PH (2004) In-vitro activity of nikkomycin Z alone and in combination with polyenes, triazoles or echinocandins against Aspergillus fumigatus. Clin Microbiol Infect 10:961–966
Gao X, Haynes SW, Ames BD, Wang P, Vien L, Walsh CT, Tang Y (2012) Cyclization of fungal nonribosomal peptides by a terminal condensation-like domain. Nat Chem Biol 8:823–830
Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS (2008) A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility. Antimicrob Agents Chemother 52:2305–2312
Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS (2009a) Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-(beta)-D-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob Agents Chemother 53:3690–3699
Garcia-Effron G, Park S, Perlin DS (2009b) Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints. Antimicrob Agents Chemother 53:112–122
Garcia-Effron GS, Park S, Perlin DS (2011) Improved detection of Candida sp. fks hot spot mutants by using the method of the CLSI M27-A3 Document with the addition of bovine serum albumin. Antimicrob Agents Chemother 55:2245–2255
Gardiner RE, Souteropoulos P, Park S, Perlin DS (2005) Characterization of Aspergillus fumigatus mutants with reduced susceptibility to caspofungin. Med Mycol 43:S299–S305
Geiser DM, Klich MA, Frisvad JC, Peterson SW, Varga J, Samson RA (2007) The current status of species recognition and identification in Aspergillus. Stud Mycol 59:1–10
Ghannoum M, D’Angelo M (2005) Anidulafungin: a potent antifungal that targets candida and aspergillus. Infect Dis Clin Prac 13:165–178
Gil C, Pérez-Diaz R, Nombela C (1994) Inhibitory and morphological effects of several antifungal agents on three types of Candida albicans morphological mutants. J Med Vet Mycol 32:151–162
Gordee RS, Zeckner DJ, Howard LC, Alborn WE Jr, Debono M (1988) Anti-Candida activity and toxicology of LY121019, a novel semisynthetic polypeptide antifungal antibiotic. Ann N Y Acad Sci 544:294–309
Hansen DB, Bumpus SB, Aron ZD, Kelleher NL, Walsh CT (2007) The loading module of mycosubtilin: an adenylation domain with fatty acid selectivity. J Am Chem Soc 129:6366–6367
Hao B, Cheng S, Clancy CJ, Nguyen MH (2012) Caspofungin kills Candida albicans by causing both cellular apoptosis and necrosis. Antimicrob Agents Chemother. doi:10.1128/AAC.01366-12
Hensens OD, Liesch JM, Zink DL, Smith JL, Wichmann CF, Schwartz RE (1992) Pneumocandins from Zalerion arboricola. III. Structure elucidation. J Antibiot 45:1875–1885
Hino M, Fujie A, Iwamoto T, Hori Y, Hashimoto M, Tsurumi Y, Sakamoto K, Takase S, Hashimoto S (2001) Chemical diversity in lipopeptide antifungal antibiotics. J Ind Microbiol Biotechnol 27:157–162
Hodges RL, Hodges DW, Goggans K, Xuei X, Skatrud P, McGilvray D (1994) Genetic modification of an echinocandin B-producing strain of Aspergillus nidulans to produce mutants blocked in sterigmatocystin biosynthesis. J Ind Microbiol 13:372–381
Hodges RL, Kelkar HS, Xuei X, Skatrud PL, Keller NP, Adams TH, Kaiser RE, Vinci VA, McGilvray D (2000) Characterization of an echinocandin B-producing strain blocked for sterigmatocystin biosynthesis reveals a translocation in the stcW gene of the aflatoxin biosynthetic pathway. J Ind Microbiol Biotechnol 25:333–341
Hoffmann D, Hevel JM, Moore RE, Moore BS (2003) Sequence analysis and biochemical characterization of the nostopeptolide A biosynthetic gene cluster from Nostoc sp. GSV224. Gene 311:171–180
Hormigo D, de la Mata I, Acebal C, Arroyo M (2010) Immobilized aculeacin A acylase from Actinoplanes utahensis: characterization of a novel biocatalyst. Bioresour Technol 101:4261–4268
Howard SJ, Arendrup MC (2011) Acquired antifungal drug resistance in Aspergillus fumigatus: epidemiology and detection. Med Mycol 49:S90–S95
Imtiaz T, Lee KK, Munro CA, Maccallum DM, Shankland GS, Johnson EM, Macgregor MS, Bal AM (2012) Echinocandin resistance due to simultaneous FKS mutation and increased cell wall chitin in a Candida albicans bloodstream isolate following brief exposure to caspofungin. J Med Microbiol 61:1330–1334
Inokoshi J, Takeshima H, Ikeda H, Omura S (1992) Cloning and sequencing of the aculeacin A acylase-encoding gene from Actinoplanes utahensis and expression in Streptomyces lividans. Gene 119:29–35
Ishihara S, Hirata A, Nogami S, Beauvais A, Latge JP, Ohya Y (2007) Homologous subunits of 1,3-beta-glucan synthase are important for spore wall assembly in Saccharomyces cerevisiae. Eukaryot Cell 6:143–156
Iwamoto T, Fujie A, Sakamoto K, Tsurumi Y, Shigematsu N, Yamashita M, Hashimoto S, Okuhara M, Kohsaka M (1994) WF11899A, B and C, novel antifungal lipopeptides, I: taxonomy, fermentation, isolation and physico-chemical properties. J Antibiot 47:1084–1091
Johnson ME, Katiyar SK, Edlind TD (2011) New Fks hot spot for acquired echinocandin resistance in Saccharomyces cerevisiae and its contribution to intrinsic resistance of Scedosporium species. Antimicrob Agents Chemother 55:3774–3781
Kanafani ZA, Perfect JR (2008) Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact. Clin Infect Dis 46:120–128
Kanasaki R, Abe F, Kobayashi M, Katsuoka M, Hashimoto M, Takase S, Tsurumi Y, Fujie A, Hino M, Hashimoto S, Hori Y (2006a) FR220897 and FR220899, novel antifungal lipopeptides from Coleophoma empetri no. 14573. J Antibiot 59:149–157
Kanasaki R, Kobayashi M, Fujine K, Sato I, Hashimoto M, Takase S, Tsurumi Y, Fujie A, Hino M, Hashimoto S, Hori Y (2006b) FR227673 and FR190293, novel antifungal lipopeptides from Chalara sp. No. 22210 and Tolypocladium parasiticum No. 16616. J Antibiot 59:158–167
Kanasaki R, Sakamoto K, Hashimoto M, Takase S, Tsurumi Y, Fujie A, Hino M, Hashimoto S, Hori Y (2006c) FR209602 and related compounds, novel antifungal lipopeptides from Coleophoma crateriformis no.738. I. Taxonomy, fermentation, isolation and physico-chemical properties. J Antibiot 59:137–144
Kanda M, Tsuboi M, Sakamoto K, Shimizu S, Yamashita M, Honda H (2009) Improvement of FR901379 production by mutant selection and medium optimization. J Biosci Bioeng 107:530–534
Kanda M, Yamamoto E, Hayashi A, Yabutani T, Yamashita M, Honda H (2010) Scale-up fermentation of echinocandin type antibiotic FR901379. J Biosci Bioeng 109:138–144
Katiyar S, Pfaller M, Edlind T (2006) Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility. Antimicrob Agents Chemother 50:2892–2894
Katiyar SK, Edlind TD (2009) Role for Fks1 in the intrinsic echinocandin resistance of Fusarium solani as evidenced by hybrid expression in Saccharomyces cerevisiae. Antimicrob Agents Chemother 53:1772–1778
Katiyar SK, Alastruey-Izquierdo A, Healey KR, Johnson ME, Perlin DS, Edlind TD (2012) Fks1 and Fks2 are functionally redundant but differentially regulated in Candida glabrata: implications for echinocandin resistance. Antimicrob Agents Chemothe 56:6304–6309
Kauss H, Jeblick W (1986) Influence of free fatty acids, lysophosphatidylcholine, platelet-activating factor, acylcarnitine, and echinocandin B on 1,3-beta-D-glucan synthase and callose synthesis. Plant Physiol 80:7–13
Keller-Juslén C, Kuhn M, Loosli HR, Petcher TJ, Weber HP, von Wartburg A (1976) Struktur des cyclopeptid-antibiotikums sl 7810 (= echinocandinb). Tetrahedron Lett 17:4147–4150
Klein LL, Li L, Chen HJ, Curty CB, DeGoey DA, Grampovnik DJ, Leone CL, Thomas SA, Yeung CM, Funk KW, Kishore V, Lundell EO, Wodka D, Meulbroek JA, Alder JD, Nilius AM, Lartey PA, Plattner JJ (2000) Total synthesis and antifungal evaluation of cyclic aminohexapeptides. Bioorg Med Chem 8:1677–1696
Klich M, Mendoza C, Mullaney E, Keller N, Bennett JW (2001) A new sterigmatocystin-producing Emericella variant from agricultural desert soils. Syst Appl Microbiol 24:131–138
Kofla G, Ruhnke M (2011) Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature. Eur J Med Res 16:159–166
Kraas FI, Helmetag V, Wittmann M, Strieker M, Marahiel MA (2010) Functional dissection of surfactin synthetase initiation module reveals insights into the mechanism of lipoinitiation. Chem Biol 17:872–880
Kurtz MB, Douglas C, Marrinan J, Nollstadt K, Onishi J, Dreikorn S, Milligan J, Mandala S, Thompson J, Balkovec JM, Bouffard FA, Dropinski JF, Hammond ML, Zambias RA, Abruzzo G, Bartizal K, McManus OB, Garcia ML (1994a) Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis. Antimicrob Agents Chemother 38:2750–2757
Kurtz MB, Heath IB, Marrinan J, Dreikorn S, Onishi J, Douglas C (1994b) Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activity against (1,3)-β-D-glucan synthase. Antimicrob Agents Chemother 38:1480–1489
Lal B, Gund VG, Gangopadhyay AK, Nadkarni SR, Dikshit V, Chatterjee DK, Shirvaikar R (2003) Semisynthetic modifications of hemiaminal function at ornithine unit of mulundocandin, towards chemical stability and antifungal activity. Bioorg Med Chem 11:5189–5198
Lamoth F, Juvvadi PR, Gehrke C, Steinbach WJ (2012) In vitro activity of calcineurin and heat-shock protein 90 (HSP90) inhibitors against Aspergillus fumigatus azole- and echinocandin-resistant strains. Antimicrob Agents Chemother. doi:10.1128/AAC.01857-12
Lee KK, Maccallum DM, Jacobsen MD, Walker LA, Odds FC, Gow NA, Munro CA (2012) Elevated cell wall chitin in Candida albicans confers echinocandin resistance in vivo. Antimicrob Agents Chemother 56:208–217
Leonard WR Jr, Belyk KM, Conlon DA, Bender DR, DiMichele LM, Liu J, Hughes DL (2007) Synthesis of the antifungal beta-1,3-glucan synthase inhibitor CANCIDAS (caspofungin acetate) from pneumocandin B0. J Org Chem 72:2335–2343
Maligie MA, Selitrennikoff CP (2005) Cryptococcus neoformans resistance to echinocandins: (1,3)beta-glucan synthase activity is sensitive to echinocandins. Antimicrob Agents Chemother 49:2851–2856
Martos AI, Romero A, González MT, González A, Serrano C, Castro C, Pemán J, Cantón E, Martín-Mazuelos E (2010) Evaluation of the Etest method for susceptibility testing of Aspergillus spp. and Fusarium spp. to three echinocandins. Med Mycol 48:858–861
Masurekar PS, Fountoulakis JM, Hallada TC, Sosa MS, Kaplan L (1992) Pneumocandins from Zalerion arboricola. II. Modification of product spectrum by mutation and medium manipulation. J Antibiot 45:1867–1874
Mazur P, Morin N, Baginsky W, el Sherbeini M, Clemas JA, Nielsen JB, Foor F (1995) Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase. Mol Cell Biol 15:5671–5681
Mishra BB, Tiwari VK (2011) 1. Natural products in drug discovery: clinical evaluations and investigations. In: Tiwari VK, Mishra BB (eds) Opportunity, challenge and scope of natural products in medicinal chemistry. Research Signpost, Kerala, pp 1–62
Mizoguchi J, Saito T, Mizuno K, Hayano K (1977) On the mode of action of the new antifungal agent, aculeacin A: inhibition of cell wall synthesis in Saccharomyces cerevisiae. J Antibiot 30:308–313
Mizuno K, Yagi A, Satoi S, Takada M, Hayashi M, Asano K, Matsuda T (1977) Studies I. Isolation and characterization of aculeacin A. J Antibiot 30:297–302
Morris SA, Schwartz RE, Sesin DF, Masurekar P, Hallada TC, Schmatz DM, Bartizal K, Hensens OD, Zink DL (1994) Pneumocandin D0, a new antifungal agent and potent inhibitor of Pneumocystis carinii. J Antibiot 47:755–764
Mukherjee PK, Sheehan D, Puzniak L, Schlamm H, Ghannoum MA (2011) Echinocandins: are they all the same? J Chemother 23:319–325
Mukhopadhyay T, Ganguli BN, Fehlhaber HW, Kogler H, Verfesy L (1987) Mulundocandin, a new lipopeptide antibiotic. II. Structure elucidation. J Antibiot 40:281–289
Mukhopadhyay T, Roy K, Bhat RG, Sawant SN, Blumbach J, Gangtjli BN, Fehlhaber HW (1992) Deoxymulundocandin-A new echinocandin type antifungal antibiotic. J Antibiot 45:618–623
Niimi K, Maki K, Ikeda F, Holmes AR, Lamping E, Niimi M, Monk BC, Cannon RD (2006) Overexpression of Candida albicans CDR1, CDR2, or MDR1 does not produce significant changes in echinocandin susceptibility. Antimicrob Agents Chemother 50:1148–1155
Nobel HM, Langley D, Sidebottom PJ, Lane SJ, Fisher PJ (1991) An echinocandin from an endophytic Cryptosporiopsis sp. and Pezicula sp. In Pinus sylvestris and Fagus sylvatica. Mycol Res 95:1439–1440
Nyfeler R, Keller SW (1974) Metabolites of microorganisms, 143: echinocandin B, a novel polypeptide-antibiotic from Aspergillus nidulans var echinulatus—isolation and structural components. Helv Chim Acta 57:2459–2477
Odabasi Z, Paetznick V, Rex JH, Ostrosky-Zeichner L (2007) Effects of serum on in vitro susceptibility testing of echinocandins. Antimicrob Agents Chemother 51:4214–4216
Paderu P, Park S, Perlin DS (2004) Caspofungin uptake is mediated by a high-affinity transporter in Candida albicans. Antimicrob Agents Chemother 48:3845–3849
Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS (2007) Serum differentially alters the antifungal properties of echinocandin drugs. Antimicrob Agents Chemother 51:2253–2256
Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, Filler SG, Fisher JF, Kullberg BJ, Ostrosky-Zeichner L, Reboli AC, Rex JH, Walsh TJ, Sobel JD (2009) Infectious Diseases Society of America: Clinical Practice Guidelines for the management of candidiasis: update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535
Park S, Kelly R, Kahn JN, Robles J, Hsu MJ, Register E, Li W, Vyas V, Fan H, Abruzzo G, Flattery A, Gill C, Chrebet G, Parent SA, Kurtz M, Teppler H, Douglas CM, Perlin DS (2005) Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother 49:3264–3273
Perez P, Varona R, Garcia-Acha I, Duran A (1981) Effect of papulacandin B and aculeacin A on [Beta]-(1,3)-glucan-synthase from Geotrichum lactis. FEBS Lett 129:249–252
Perlin DS (2007) Resistance to echinocandin-class antifungal drugs. Drug Resist Updat 10:121–130
Perlin DS (2011) Current perspectives on echinocandin class drugs. Future Microbiol 6:441–457
Petersen LA, Hughes DL, Hughes R, DiMichele L, Salmon P, Connors N (2001) Effects of amino acid and trace element supplementation on pneumocandin production by Glarea lozoyensis: impact on titer, analogue levels, and the identification of new analogues of pneumocandin B(0). J Ind Microbiol Biotechnol 26:216–221
Petersen LA, Olewinski R, Salmon P, Connors N (2003) Novel proline hydroxylase activities in the pneumocandin-producing fungus Glarea lozoyensis responsible for the formation of trans 3- and trans 4-hydroxyproline. Appl Microbiol Biotechnol 62:263–267
Peterson SW (2008) Phylogenetic analysis of Aspergillus species using DNA sequences from four loci. Mycologia 100:205–226
Petraitiene R, Petraitis V, Groll AH, Candelario M, Sein T, Bell A, Lyman CA, McMillian CL, Bacher J, Walsh TJ (1999) Antifungal activity of LY303366, a novel echinocandin B, in experimental disseminated candidiasis in rabbits. Antimicrob Agents Chemother 43:2148–2155
Pfaller MA (2012) Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med 125:S3–S13
Pfaller MA, Diekema DJ (2009) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163
Pfaller M, Riley J, Koerner T (1989) Effect of cilofungin (LY121019) on carbohydrate and sterol composition of Candida albicans. Eur J Clin Microbiol Infect Dis 8:1067–1070
Pfaller MA, Castanheira M, Messer SA, Moet GJ, Jones RN (2011a) Echinocandin and triazole antifungal susceptibility profiles for Candida spp., Cryptococcus neoformans, and Aspergillus fumigatus: application of new CLSI clinical breakpoints and epidemiologic cutoff values to characterize resistance in the SENTRY Antimicrobial Surveillance Program (2009). Diagn Microbiol Infect Dis 69:45–50
Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, Motyl M, Perlin DS, the CLSI Subcommittee for Antifungal Testing (2011b) Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat 14:164–176
Pfaller MA, Castanheira M, Lockhart SR, Ahlquist AM, Moet GJ, Messer SA, Woosley LN, Jones RN (2012) Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata: results from the SENTRY Antimicrobial Surveillance Program (2006–2010) and the Centers for Disease Control and Prevention Population-Based Surveillance (2008–2010). J Clin Microbiol. doi:10.1128/JCM.06112-11
Plaine A, Walker L, Da Costa G, Mora-Montes HM, McKinnon A, Gow NA, Gaillardin C, Munro CA, Richard ML (2008) Functional analysis of Candida albicans GPI-anchored proteins: roles in cell wall integrity and caspofungin sensitivity. Fungal Genet Biol 45:1404–1414
Pollard DJ, Kirschner TF, Hernandez D, Hunt G, Olewinski R (2002) Pilot-scale process sensitivity studies for the scaleup of a fungal fermentation for the production of Pneumocandins. Biotechnol Bioeng 78:270–279
Pollard DJ, Kirschner TF, Hunt GR, Tong IT, Stieber R, Salmon PM (2007) Scale up of a viscous fungal fermentation. application of scale-up criteria with regime analysis and operating boundary conditions. Biotechnol Bioeng 96:307–317
Radding JA, Heidler SA, Turner W (1998) Photoaffinity analog of the semisynthetic echinocandin LY303366: identification of echinocandin targets in Candida albicans. Antimicrob Agents Chemother 42:1187–1194
Rank C, Nielsen KF, Larsen TO, Varga J, Samson RA, Frisvad JC (2011) Distribution of sterigmatocystin in filamentous fungi. Fungal Biol 115:406–420
Rocha EM, Garcia-Effron G, Park S, Perlin DS (2007) A Ser678Pro substitution in Fks1p confers resistance to echinocandin drugs in Aspergillus fumigatus. Antimicrob Agents Chemother 51:4174–4176
Romano J, Nimrod G, Ben-Tal N, Shadkchan Y, Baruch K, Sharon H, Osherov N (2006) Disruption of the Aspergillus fumigatus ECM33 homologue results in rapid conidial germination, antifungal resistance and hypervirulence. Microbiology 152:1919–1928
Roy K, Mukhopadhyay T, Reddy GC, Desikan KR, Ganguli BN (1987) Mulundocandin, a new lipopeptide antibiotic. I. Taxonomy, fermentation, isolation and characterization. J Antibiot 40:275–280
Rüping MJGD, Vehreschild JJ, Cornely OA (2008) Patients at high risk of invasive fungal infections-when at how to treat. Drugs 68:1941–1962
Satoi S, Yagi A, Asano K, Mizuno K, Watanabe T (1977) Studies on aculeacin. II. Isolation and characterization of aculeacins B, C, D, E, F and G. J Antibiot 30:303–307
Sawistowska-Schröder ET, Kerridge D, Perry H (1984) Echinocandin inhibition of 1,3-beta-D-glucan synthase from Candida albicans. FEBS Lett 173:134–138
Schmatz DM, Abruzzo G, Powles MA, McFadden DC, Balkovec JM, Black RM, Nollstadt K, Bartizal K (1992) Pneumocandins from Zalerion arboricola. IV. Biological evaluation of natural and semisynthetic pneumocandins for activity against Pneumocystis carinii and Candida species. J Antibiot 45:1886–1891
Schwartz RE, Giacobbe RA, Bland JA, Monaghan RL (1989) L-671,329, a new antifungal agent. I. Fermentation and isolation. J Antibiot 42:163–167
Schwartz RE, Sesin DF, Joshua H, Wilson KE, Kempf AJ, Goklen KA, Kuehner D, Gailliot P, Gleason C, White R, Inamine E, Bills G, Salmon P, Zitano L (1992) Pneumocandins from Zalerion arboricola. Discovery and isolation I. J Antibiot 45:1853–1866
Scott LJ (2012) Micafungin: a review of its use in the prophylaxis and treatment of invasive Candida infections. Drugs 72:2141–2165
Shields RK, Nguyen MH, Press E, Clancy CJ (2011a) Five-minute exposure to caspofungin results in prolonged post-antifungal effects and eliminates the paradoxical growth of Candida albicans. Antimicrob Agents Chemother 55:3598–36023
Shields RK, Nguyen MH, Du C, Press E, Cheng S, Clancy CJ (2011b) Paradoxical effect of caspofungin against Candida bloodstream isolates is mediated by multiple pathways but eliminated in human serum. Antimicrob Agents Chemother 55:2641–2647
Singh SD, Robbins N, Zaas AK, Schell WA, Perfect JR, Cowen LE (2009) Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog 5:e1000532
Singh-Babak SD, Babak T, Diezmann S, Hill JA, Xie JL, Chen YL, Poutanen SM, Rennie RP, Heitman J, Cowen LE (2012) Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog 8:e1002718
Sóczó G, Kardos G, Varga I, Kelentey B, Gesztelyi R, Majoros L (2007) In vitro study of Candida tropicalis isolates exhibiting paradoxical growth in the presence of high concentrations of caspofungin. Antimicrob Agents Chemother 51:4474–4476
Stevens DA, Ichinomiya M, Koshi Y, Horiuchi H (2006) Escape of Candida from caspofungin inhibition at concentrations above the MIC (paradoxical effect) accomplished by increased cell wall chitin; evidence for beta-1,6-glucan synthesis inhibition by caspofungin. Antimicrob Agents Chemother 50:3160–3161
Stone BA, Clarke AE (1992) The chemistry and biology of (13)-β-glucans. La Trobe University Press, Melbourne
Strobel GA, Miller RV, Martinez-Miller C, Condron MM, Teplow DB, Hess WM (1999) Cryptocandin, a potent antimycotic from the endophytic fungus Cryptosporiopsis cf. quercina. Microbiology 145:1919–1926
Szilágyi J, Földi R, Bayegan S, Kardos G, Majoros L (2012) Effect of nikkomycin Z and 50 % human serum on the killing activity of high-concentration caspofungin against Candida species using time-kill methodology. J Chemother 24:18–25
Taft CS, Stark T, Sellitrennikoff CP (1988) Cilofungin (LYI21019) inhibits Neurospora crassa growth and (1–3)-[Beta]-D-glucan synthase activity. J Antibiot 41:697–701
Takeshima H, Inokoshi J, Takada Y, Tanaka H, Omura S (1989) A deacylation enzyme for aculeacin A, a neutral lipopeptide antibiotic, from Actinoplanes utahensis: purification and characterization. J Biochem 105:606–610
Tang J, Parr TR (1991) W-1 solubilization and kinetics of inhibition by cilofungin of Candida albicans (1,3)-[Beta]-glucan synthase. Antimicrob Agents Chemother 35:99–103
Tkacz JS, Giacobbe RA, Monaghan RL (1993) Improvement in the titer of echinocandin-type antibiotics: a magnesium-limited medium supporting the biphasic production of pneumocandins A0 and B0. J Ind Microbiol 11:95–103
Torres-Bacete J, Hormigo D, Stuart M, Arroyo M, Torres P, Castillón MP, Acebal C, García JL, de la Mata I (2007) Newly discovered penicillin acylase activity of aculeacin A acylase from Actinoplanes utahensis. Appl Environ Microbiol 73:5378–5381
Tóth V (2012) Characterization of Aspergillus nidulans var. roseus ATCC 58397, investigation its echinocandin B and sterigmatocystin production. Dissertation, University of Debrecen
Tóth V, CsT N, Miskei M, Pócsi I, Emri T (2011) Polyphasic characterization of “Aspergillus nidulans var. roseus” ATCC 58397. Folia Microbiol 56:381–388
Tóth V, CsT N, Pócsi I, Emri T (2012) The echinocandin B producer fungus Aspergillus nidulans var. roseus ATCC 58397 does not possess innate resistance against its lipopeptide antimycotic. Appl Microbiol Biotechnol 95:113–122
Traber R, Keller-Juslén C, Loosli HR, Kuhn M, Von Wartburg A (1979) Cyclopeptid-Antibiotika aus Aspergillus-Arten. Struktur der Echinocandine C und D. Helv Chim Acta 62:1252–1267
Tscherter H, Dreyfuss MM (1982) New metabolites. Processes for their production and their use. Internat. Patent Appl PCT/EP8/00121
Ueda S, Sakamoto K, Oohata N, Tsuboi M, Yamashita M, Hino M, Yamada M, Hashimoto S (2010) Screening and characterization of microorganisms with FR901379 acylase activity. J Antibiot 63:65–70
Ueda S, Kinoshita M, Tanaka F, Tsuboi M, Shimizu S, Oohata N, Hino M, Yamada M, Isogai Y, Hashimoto S (2011a) Strain selection and scale-up fermentation for FR901379 acylase production by Streptomyces sp. no. 6907. J Biosci Bioeng 112:409–414
Ueda S, Shibata T, Ito K, Oohata N, Yamashita M, Hino M, Yamada M, Isogai Y, Hashimoto S (2011b) Cloning and expression of the FR901379 acylase gene from Streptomyces sp. no. 6907. J Antibiot 64:169–175
van de Sande WW, Fahal AH, Bakker-Woudenberg IA, van Belkum A (2010) Madurella mycetomatis is not susceptible to the echinocandin class of antifungal agents. Antimicrob Agents Chemother 54:2738–2740
van Duin D, Casadevall A, Nosanchuk JD (2002) Melanization of Cryptococcus neoformans and Histoplasma capsulatum reduces their susceptibilities to amphotericin B and caspofungin. Antimicrob Agents Chemother 46:3394–3400
Vazquez JA, Lynch M, Sobel JD (1995) In vitro activity of a new pneumocandin antifungal agent, L-733,560 against azole-susceptible and -resistant Candida and Torulopsis species. Antimicrob Agents Chemother 39:2689–2691
Verwer PE, van Duijn ML, Tavakol M, Bakker-Woudenberg IA, van de Sande WW (2012) Reshuffling of Aspergillus fumigatus cell wall components chitin and β-glucan under the influence of caspofungin or nikkomycin Z alone or in combination. Antimicrob Agents Chemother 56:1595–1598
Walker LA, Munro CA, de Bruijn I, Lenardon MD, McKinnon A, Gow NA (2008) Stimulation of chitin synthesis rescues Candida albicans from echinocandins. PLoS Pathog 4(4):e1000040
Walker LA, Gow NAR, Munro CA (2010) Fungal echinocandin resistance. Fungal Genet Biol 47:117–126
Walker LA, Gow NA, Munro CA (2012) Elevated chitin content reduces the susceptibility of Candida species to caspofungin. Antimicrob Agents Chemother. doi:10.1128/AAC.01486-12
Wiederhold NP (2007) Attenuation of echinocandin activity at elevated concentrations: a review of the paradoxical effect. Curr Opin Infect Dis 20:574–578
Wittmann M, Linne U, Pohlmann V, Marahiel MA (2008) Role of DptE and DptF in the lipidation reaction of daptomycin. FEBS J 275:5343–5354
Yamaguchi H, Hiratani T, Iwata K, Yamamoto Y (1982) Studies on the mechanism of antifungal action of aculeacin A. J Antibiot 35:210–219
Yamaguchi H, Hiratani T, Baba MN, Osumi M (1985) Effect of aculeacin A, a wall-active antibiotic, on synthesis of the yeast cell wall. Microbiol Immunol 29:609–623
Yao J, Liu H, Zhou T, Chen H, Miao Z, Sheng C, Zhang W (2012) Total synthesis and structure–activity relationships of new echinocandin-like antifungal cyclolipohexapeptides. Eur J Med Chem 50:196–208
Youssar L, Grüning BA, Erxleben A, Günther S, Hüttel W (2012) Genome sequence of the fungus Glarea lozoyensis: the first genome sequence of a species from the Helotiaceae family. Eukaryot Cell 11:250, Erratum in: Eukaryot Cell 11:829
Zambias RA, Hammond ML, Heck JV, Bartizal K, Trainor C, Abruzzo G, Schmatz DM, Nollstadt KM (1992) Preparation and structure relationships of simplified analogues of the antifungal agent cilofungin: a total synthesis approach. J Med Chem 35:2843–2855
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This work was supported by the TAMOP 4.2.1/B-09/1/KONV-2010-0007, TAMOP-4.2.2/B-10/1-2010-0024 and TÁMOP-4.2.2.A-11/1/KONV-2012-0045 projects and was implemented through the New Hungary Development Plan, co-financed by the European Union and the European Social Fund.
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Emri, T., Majoros, L., Tóth, V. et al. Echinocandins: production and applications. Appl Microbiol Biotechnol 97, 3267–3284 (2013). https://doi.org/10.1007/s00253-013-4761-9
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DOI: https://doi.org/10.1007/s00253-013-4761-9