International Journal of Antimicrobial Agents 33 (2009) 285–286
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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
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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 . 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 . 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  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  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 , 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)
With 50% FCS
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.
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