Antifungal activity of anidulafungin, a product of Aspergillus nidulans, against Aspergillus nidulans

Antifungal activity of anidulafungin, a product of Aspergillus nidulans, against Aspergillus nidulans

International Journal of Antimicrobial Agents 33 (2009) 285–286 Contents lists available at ScienceDirect International Journal of Antimicrobial Age...

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International Journal of Antimicrobial Agents 33 (2009) 285–286

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag

Short communication

Antifungal activity of anidulafungin, a product of Aspergillus nidulans, against Aspergillus nidulans H. Hof ∗ , A. Dietz Institute of Medical Microbiology and Hygiene, University Clinic Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, D-68167 Mannheim, Germany

a r t i c l e

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Article history: Received 16 July 2008 Accepted 12 August 2008 Keywords: Anidulafungin Aspergillus nidulans Growth inhibition

a b s t r a c t Anidulafungin is a semisynthetic product originating from Aspergillus nidulans. The aim of this study was to determine whether this drug is active against A. nidulans strains. The minimum effective concentration (MEC) of anidulafungin without and with 50% foetal calf serum was determined according to the Clinical and Laboratory Standards microdilution method. All 13 A. nidulans strains were highly susceptible to anidulafungin, with a MEC of 0.031 mg/L. The presence of serum did not affect the in vitro activity. In conclusion, chemical modification of the original echinocandin B moiety renders this natural product active against moulds, including A. nidulans. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction Anidulafungin, formerly LY303,366, is a semisynthetic derivative of a natural product class of antifungal agents produced by Aspergillus nidulans belonging to the class of drugs known as echinocandin type B [1,2]. The haemolytic property of the native echinocandins can be greatly reduced by enzymatically creating analogues of echinocandin B; at the same time the antimicrobial activity of some of the compounds can be enhanced [3]. Several derivatives with a similar ring moiety but different side chains have been developed for therapeutic use (Fig. 1). Echinocandins are non-competitive inhibitors of the fungal (1,3)-␤-d-glucan synthase, which produces glucan polymers, a major component of the fungal cell wall [4]. Anidulafungin has been reported to have excellent activity against a wide range of fungal pathogens, including yeasts [5–9] and moulds, amongst them several Aspergillus spp. [6,10]. The question arises whether this semisynthetic compound is also active against A. nidulans or whether this species is generally resistant to this drug, since the core of drug is a natural product of A. nidulans. Until now, only three strains have been tested and found to be susceptible [6,11]. 2. Materials and methods The minimum effective concentration (MEC) values of anidulafungin for 13 strains of A. nidulans isolated from the environment

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(10 strains were kindly provided by Prof. G. Fischer, University of Aachen, Germany) were determined according to the Clinical and Laboratory Standards Institute microdilution method [12] following incubation at 35 ◦ C for 24 h or 48 h, respectively, in RPMI 1640 with MOPS buffer without or with 50% foetal calf serum (FCS), since the in vitro activity of anidulafungin [9,13] as well as other echinocandins [14] against Candida spp. may be modulated by serum. Reference strains of Candida parapsilosis, Candida albicans and Aspergillus flavus (Table 1) were used as controls. 3. Results Anidulafungin exerted a high activity against several yeasts, except C. parapsilosis. Furthermore, A. flavus was equally susceptible. All 13 strains of A. nidulans displayed low MEC values at 24 h and 48 h of 0.031 mg/L, similar to those seen with C. albicans and A. flavus (Table 1). The minimum inhibitory concentration of C. parapsilosis increased significantly when 50% FCS was added to the culture medium, but serum did not influence the in vitro activity against A. nidulans (Table 1). Even at rather high drug concentrations exceeding the MEC values, growth of A. nidulans was not completely inhibited owing to the fact that anidulafungin exerts a fungistatic rather than a fungicidal effect against Aspergillus spp. in general [4,15]. 4. Discussion The paradoxical high activity of anidulafungin against A. nidulans is most probably due to the fact that the natural fungal product, echinocandin B, which possesses strong activity against Candida spp. but not against moulds [1], acquires an additional

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H. Hof, A. Dietz / International Journal of Antimicrobial Agents 33 (2009) 285–286

Fig. 1. Structural formulae of the echinocandins anidulafungin, caspofungin and micafungin. Table 1 In vitro activity of anidulafungin against various yeasts (MIC) and filamentous fungi (MEC). Strain

Candida parapsilosis ATCC 22019 Candida albicans ATCC 90028 Aspergillus flavus ATCC 204304 Aspergillus nidulans (n = 13)

MIC/MEC after 24 h (mg/L)

MIC/MEC after 48 h (mg/L)

Without serum

With 50% FCS

Without serum

With 50% FCS

1.0 0.031 0.031 0.031

16 0.031 0.031 0.031

1.0 0.031 0.031 0.031

16 0.031 0.031 0.031

MIC, minimum inhibitory concentration; MEC, minimum effective concentration; FCS, foetal calf serum.

property due to chemical modification of the core molecule. This renders the drug active even against its producer strains. Funding: No funding sources. Competing interests: Speaker’s bureau: Pfizer, MSD, Gilead, Schering Plough; Advisory board: MSD, Gilead. Ethical approval: Not required. References [1] Benz F, Knuesel F, Nuesch J, Treichler H, Voser W, Nyfeler R, et al. Echinocandin B, a new polypeptide antibiotic from Aspergillus nidulans var. echinulatus: isolation and components [in German]. Helv Chim Acta 1985;57:2459–77. [2] Hodges RL, Kelkar HS, Xuei X, Skatrud PL, Keller NP, Adams TH, et al. 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 2000;25:333–41. [3] De Lucca AJ, Walsh TJ. Antifungal peptides: novel therapeutic compounds against emerging pathogens. Antimicrob Agents Chemother 1999;43: 1–11. [4] Denning DW. Echinocandin antifungal drugs. Lancet 2003;362:1142–51. [5] Laverdiere M, Labbé AC, Restieri C, Rotstein C, Heyland D, Madger S, et al. Susceptibility patterns of Candida species recovered from Canadian intensive care units. J Crit Care 2007;22:245–50. [6] Oakley KL, Moore CB, Denning DW. In vitro activity of the echinocandin antifungal agent LY303,366 in comparison with itraconazole and amphotericin B against Aspergillus spp. Antimicrob Agents Chemother 1998;42:2726–30.

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