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Antimicrobial Agents and Chemotherapy, October 2003, p. 3281-3289, Vol. 47, No. 10
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.10.3281-3289.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Fungal Cell Wall Septation and Cytokinesis Are Inhibited by Bleomycins

Department of Microbiology and Immunology, City University of New York Medical School and Sophie Davis School of Biomedical Education, and Graduate Programs in Biochemistry and Molecular, Cellular, and Developmental Biology, New York, New York 10031,¹ Memorial Sloan-Kettering Cancer Center, New York, New York 10021,² Department of Pathology, Mount Sinai School of Medicine, New York, New York 10029-6574³

Received 11 April 2003/ Returned for modification 1 June 2003/ Accepted 2 July 2003

When the essential and distinctive cell walls of either pathogenic or nonpathogenic fungi break, cytoplasmic membranes rupture and fungi die. This fungicidal activity was discovered previously on nonproliferating Saccharomyces cerevisiae cells treated briefly with the oxidative tool and anticancer drug family of bleomycins. The present studies investigated effects of bleomycin on growing fungal organisms. These included the medically important Aspergillus fumigatus and Cryptococcus neoformans, as well as the emerging human pathogen and fungal model, S. cerevisiae. Bleomycin had its highest potency against A. fumigatus. Scanning electron microscopy and thin-section transmission electron microscopy were used to study morphological growth characteristics. Killing and growth inhibition were also measured. Long, thin, and segmented hyphae were observed when A. fumigatus was grown without bleomycin but were never observed when the mold was grown with the drug. Bleomycin arrested conidial germination, hyphal development, and the progression and completion of cell wall septation. Similarly, the drug inhibited the construction of yeast cell wall septa, preventing cytokinesis and progression in the cell division cycle of S. cerevisiae. Even when cytoplasms of mother and daughter cells separated, septation and cell division did not necessarily occur. Bizarre cell configurations, abnormally thickened cell walls at mother-daughter necks, abnormal polarized growth, large undivided cells, fragmented cells, and empty cell ghosts were also produced. This is the first report of a fungicidal agent that arrests fungal growth and development, septum formation, and cytokinesis and that also preferentially localizes to cell walls and alters isolated cell walls as well as intact cell walls on nongrowing cells.