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Synergistic Antifungal Activity of KB425796-C in Combination with Micafungin Against Aspergillus Fumigatus and Its Efficacy in Murine Infection Models

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Synergistic Antifungal Activity of KB425796-C in Combination with Micafungin Against Aspergillus Fumigatus and Its Efficacy in Murine Infection Models The Journal of Antibiotics (2013) 66, 479–484 & 2013 Japan Antibiotics Research Association All rights reserved 0021-8820/13 www.nature.com/ja ORIGINAL ARTICLE Synergistic antifungal activity of KB425796-C in combination with micafungin against Aspergillus fumigatus and its efficacy in murine infection models Hirohito Kai, Midori Yamashita, Ikuko Nakamura, Koji Yoshikawa, Kumiko Nitta, Masato Watanabe, Noriaki Inamura and Akihiko Fujie KB425796-C is a novel antifungal metabolite produced by the newly isolated bacterial strain Paenibacillus sp. No. 530603. This compound is a 40-membered macrocyclic lipopeptidolactone consisting of 12 amino acids and a 3-hydroxy-15- methylpalmitoyl moiety. KB425796-C displayed antifungal activity against micafungin-resistant fungi and was fungicidal to Trichosporon asahii in vitro. In a murine systemic infection model of T. asahii, KB425796-C showed excellent efficacy upon i.p. administration at 32 mg kg À1. In addition, KB425796-C induced morphological changes in the hyphae of Aspergillus fumigatus and had fungicidal effects in combination with micafungin. In a mouse model of septic A. fumigatus infection, although non- treated mice survived for a maximum of only 6 days, the survival rate of micafungin-treated mice (0.1 mg kg À1) increased to 20%, while the survival rate of mice treated with a combination of micafungin (0.1 mg kg À1) and KB425796-C (32 mg kg À1) increased to 100% during the 31-day post-infection period. Our findings suggest that KB425796-C is a good candidate for the treatment of aspergillosis in combination with micafungin. The Journal of Antibiotics (2013) 66, 479–484; doi:10.1038/ja.2013.57; published online 12 June 2013 Keywords: antifungal; Aspergillus; fermentation; KB425796-C; micafungin; Trichosporon INTRODUCTION synergistically in vitro and in vivo against A. fumigatus.6,7 Although The number of reported infections caused by Aspergillus species is micafungin alone does not exhibit in vitro activity against T. asahii,8 increasing each year in most developed countries.1 Disseminated the combination of micafungin and fluconazole is effective in trichosporonosis, which is most commonly caused by Trichosporon experimental infection models.9 These facts suggest that the asahii, is another severe fungal infection found predominantly in combination of two drugs with different mechanisms can be an immunocompromised patients. To date, efforts to treat systemic effective treatment against fungal infection, which is not satisfied with trichosporonosis using a single drug have not yielded completely current clinical practices. satisfactory results.2,3 In addition, as antifungal therapies are currently In a previous report, we described a novel antifungal antibiotic, limited to relatively few compounds, a need exists for the KB425796-C (Figure 1), which is a potent derivative of a bacterial development of novel, safe and effective therapeutic agents against metabolite KB425796-A. This compound is a macrocyclic lipodepsi- fungal diseases, particularly life-threatening infections caused by peptide (C81H119N19O18) that induces morphological changes, such A. fumigatus. as the swelling and bulging of the hyphae, in A. fumigatus, similar to The cell wall structure of fungi is distinct from that of mammalian the activity of nikkomycins. Here, we examined the antifungal activity cells,4,5 and therefore consists of several unique components, such as of KB425796-C against several micafungin-resistant fungal species chitin, a-andb-linked glucans, and various types of mannoproteins, and the activity in a disseminated murine model of trichosporonosis. which may be suitable antifungal targets. For example, the We further sought to elucidate the synergistic activity of KB425796-C biosynthesis of 1,3-b-glucan, a major and specific component of the in combination with micafungin in a murine model of disseminated fungal cell wall, is inhibited by the echinocandin-like lipopeptide aspergillosis. micafungin (Figure 1), which has potent antifungal activity against pathogenic Candida and Aspergillus species. In addition, among the RESULTS fungal cell wall biosynthesis enzymes, chitin synthase is competitively Checkerboard assay inactivated by nikkomycins, which are a group of nucleoside peptides. KB425796-C induced morphological changes in A. fumigatus hyphae It has been demonstrated that micafungin and nikkomycin Z act similar to those observed with KB425796-A.10 In microscopic Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan Correspondence: H Kai, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki, Ibaraki 305-8585, Japan. E-mail: [email protected] Received 5 December 2012; revised 8 April 2013; accepted 12 April 2013; published online 12 June 2013 Antifungal activity of KB425796-C HKaiet al 480 H OH O NH O OH N N 2 OH N H O N N H N H H H H HO O N N N N N O NH2 O NH HN O O O O O OO OH O NH O O O O H H2N N O HO NH O O O O HN OH N O HN OH N N N N O O H H H H OH NH NH HOO O S HO O HO micafungin KB425796-C Figure 1 Chemical structures of micafungin and KB425796-C. 1 0.8 MIC MEC 0.6 Table 1 In vitro antifungal activities and interactions of KB425796- C and micafungin against A. fumigatus 0.4 Agent alone Agent combined FIC of micafungin 0.2 KB425796-C Micafungin KB425796-C Micafungin FIC index Effect MEC (mgmlÀ1) 3.1 0.004 0.4 0.001 0.38 synergistic 0 MIC (mgmlÀ1) 450 40.5 3.1 0.001 o0.064 synergistic 0 0.2 0.4 0.6 0.8 1 FIC of KB425796-C Figure 2 Isobolograms showing the interaction between KB425796-C and micafungin against A. fumigatus. The numbers on the axes represent normalized FICs. observations, both micafungin and KB425796-C displayed fungistatic effects on hyphae when used alone. Micafungin induced truncation, 104 branching and shortening of hyphae, whereas KB425796-C treatment of hyphae caused swelling and the formation of protuberances. When the two drugs were used in combination, A. fumigatus cells exhibited 103 spherical dilatation. The isobolograms for the interactions between KB425796-C and micafungin are presented in Figure 2, and the 102 representative MICs, minimum effective concentrations (MECs) and CFU fractional inhibitory concentration (FIC) indices against A. fumigatus are presented in Table 1. Notably, a marked synergistic effect was 101 observed in MICs, which revealed that none of the treated cells were viable. 100 0 6 12 18 24 30 36 42 48 Time-kill curve study Time (h) Figure 3 shows a plot of cell viability over time for A. fumigatus cells treated with micafungin and KB425796-C alone or in combination µ mica 0.05 + KB 4 µg/ml KB 2 g/ml for 17, 24, 42 and 48 h. A synergistic antifungal effect was observed mica 0.05 + KB 2 µg/ml VRC 2 µg/ml when the two drugs were used in combination after 24 h. The µ µ combination of micafungin and KB425796-C was fungicidal and mica 0.05 g/ml VRC 1 g/ml markedly reduced the number of CFU, in contrast to the fungistatic Figure 3 Time-kill curve plots for micafungin (mica), KB425796-C (KB) effects (no reduction in CFU) observed at all examined time points and voriconazole (VRC) against A. fumigatus. The Journal of Antibiotics Antifungal activity of KB425796-C HKaiet al 481 when each drug was used alone. In addition, the fungicidal effects of Survival curves for the in vivo aspergillosis model treated with the combined treatment were more pronounced than those of KB425796-C, micafungin and nikkomycin X are shown in Figure 5. voriconazole, which is a commercially available fungicidal drug. All mice administered micafungin (0.1 mg kg À1) survived. In com- parison with the control group, mice administered KB425796-C (32 mg kg À1) were significantly protected from infection with A. In vivo antifungal activities of KB425796-C against T. asahii fumigatus (Po0.05). and A. fumigatus in murine infection models In the previous report, we have demonstrated that KB425796-C had In vivo antifungal effects of KB425796-C in combination antifungal activities against T. asahii (MEC ¼ 1.56 mgmlÀ1, Long-term survival curves for the murine aspergillosis model in MIC ¼ 3.13 mgmlÀ1)andA. fumigatus (MEC ¼ 3.13 mgmlÀ1, which mice were treated for 2 days with KB425796-C and micafungin MIC450 mgmlÀ1). Here the protective efficacy of KB425796-C in combination are shown in Figure 6. The first deaths occurred on administered intraperitoneally against murine systemic infection with day 4 post infection, with 100% of the control mice succumbing to T. asahii and A. fumigatus was examined. Survival curves for the infection by day 6. Administration of KB425796-C (32 mg kg À1) in vivo trichosporonosis model are shown in Figure 4. The ED of 50 alone did not show protective efficacy under the same conditions in a KB425796-C on day 14 after challenge was 12.5 mg kg À1.Inthis separate experiment (data not shown). Fewer mice treated with infection model, we found that a dose of 32 mg kg À1 KB425796-C micafungin died of infection than the control mice, and all mice was superior to 5 mg kg À1 micafungin (Po0.01) and equal to the treated with AMPH (1 mg kg À1) survived. Using the log-rank test, combination of 5 mg kg À1 micafungin and 1 mg kg À1 of amphoter- micafungin at a dose of 0.1 mg kg À1 significantly prolonged survival icin B (AMPH) (data not shown). compared with mice administered saline (Po0.01). Animals given a combination of micafungin (0.1 mg kg À1) and KB425796-C (32 mg kg À1) showed a trend towards prolonged survival in compar- 100 ison with those treated with micafungin (0.1 mg kg À1) alone (P ¼ 0.085; Figure 6).
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