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Antimicrobial Agents and Chemotherapy, December 2001, p. 3310-3321, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3310-3321.2001

Synergy, Pharmacodynamics, and Time-Sequenced Ultrastructural Changes of the Interaction between Nikkomycin Z and the Echinocandin FK463 against Aspergillus fumigatus

Christine C. Chiou,1,2,dagger Nikolaos Mavrogiorgos,1 Elizabeth Tillem,1 Richard Hector,3 and Thomas J. Walsh1,*

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland1; Department of Pediatrics, Veterans General Hospital Kaohsiung, Taiwan2; and University of California at San Francisco, San Francisco, California3

Received 29 September 2000/Returned for modification 24 February 2001/Accepted 10 July 2001

We investigated the potential synergy between two cell wall-active agents, the echinocandin FK463 (FK) and the chitin synthase inhibitor nikkomycin Z (NZ), against 16 isolates of filamentous fungi. Susceptibility testing was performed with a broth macrodilution procedure by NCCLS methods. The median minimal effective concentration (MEC) of FK against all Aspergillus species was 0.25 µg/ml (range, 0.05 to 0.5 µg/ml). For Fusarium solani and Rhizopus oryzae, MECs of FK were >512 µg/ml. The median MEC of NZ against Aspergillus fumigatus was 32 µg/ml (range, 8 to 64 µg/ml), and that against R. oryzae was 0.5 µg/ml (range, 0.06 to 2 µg/ml); however, for the other Aspergillus species, as well as F. solani, MECs were >512 µg/ml. A checkerboard inhibitory assay demonstrated synergy against A. fumigatus (median fractional inhibitory concentration index = 0.312 [range, 0.15 to 0.475]). The effect was additive to indifferent against R. oryzae and indifferent against other Aspergillus spp. and F. solani. We further investigated the pharmacodynamics of hyphal damage by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and examined the time-sequenced changes in hyphal ultrastructure. Significant synergistic hyphal damage was demonstrated with the combination of NZ (2 to 32 µg/ml) and FK (0.03 to 0.5 µg/ml) over a wide range of concentrations (P < 0.001). The synergistic effect was most pronounced after 12 h of incubation and was sustained through 24 h. Time-sequenced light and electron microscopic studies demonstrated that structural alterations of hyphae were profound, with marked transformation of hyphae to blastospore-like structures, in the presence of FK plus NZ, while fungi treated with a single drug showed partial recovery at 24 h. The methods used in this study may be applicable to elucidating the activity and interaction of other cell wall-active agents. In summary, these two cell wall-targeted antifungal agents, FK and NZ, showed marked time-dependent in vitro synergistic activity against A. fumigatus.

* Corresponding author. Mailing address: Bldg. 10, Rm. 13N-240, Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892. Phone: (301) 496-7103. Fax: (301) 402-0575. E-mail: walsht{at}mail.nih.gov.

dagger Present address: National Yang Min University, Taipei, Taiwan.

Antimicrobial Agents and Chemotherapy, December 2001, p. 3310-3321, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3310-3321.2001


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