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Antimicrobial Agents and Chemotherapy, October 2006, p. 3312-3316, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00628-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Inhibition of Filamentation Can Be Used To Treat Disseminated Candidiasis

Stephen P. Saville,1 Anna L. Lazzell,1 Alexander P. Bryant,2 Angelika Fretzen,2 Alex Monreal,2 Erik O. Solberg,2 Carlos Monteagudo,3 Jose L. Lopez-Ribot,1 and G. Todd Milne2*

Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, 6900 North Loop, 1604 West, San Antonio, Texas 78249,1 Microbia, Inc., 320 Bent St., Cambridge, Massachusetts 02141,2 Departmento de Patología, Facultad de Medicina y Odontología, Universidad de Valencia, 46010 Valencia, Spain3

Received 22 May 2006/ Returned for modification 28 June 2006/ Accepted 20 July 2006

Candida albicans remains the leading causative agent of invasive fungal infection. Although the importance of filamentation in C. albicans pathogenesis has been extensively investigated, in vivo studies to date have been unable to dissect the role of this developmental process in the establishment of infection versus the development of active disease as characterized by damage to the host leading to mortality. To address this issue, we genetically engineered a C. albicans tet-NRG1 strain in which filamentation and virulence can be modulated both in vitro and in vivo simply by the presence or absence of doxycycline (DOX): this strain enabled us, in a prior study, to demonstrate that yeast-form cells were able to infect the deep organs but caused no disease unless filamentation (induced by the addition of DOX) was allowed to occur. In the present study, we examined whether inhibiting filamentation (by withdrawing the DOX) at 24 or 48 h postinfection could serve as an effective therapeutic intervention against candidiasis. The results obtained indicate that DOX removal led to an alteration in the morphology of the infecting fungal cells and a dramatic increase in survival, but as with conventional antifungal drug therapy regimens, mortality rates increased markedly the longer this intervention was delayed. These observations reinforce the importance of invasive filamentous growth in causing the damage to the host and the lethality associated with active disease and suggest this process could be fruitfully targeted for the development of new antifungal agents.

* Corresponding author. Mailing address: Microbia, Inc., 320 Bent St., Cambridge, MA 02141. Phone: (617) 621-7722. Fax: (617) 494-0908. E-mail: tmilne{at}microbia.com.

Antimicrobial Agents and Chemotherapy, October 2006, p. 3312-3316, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00628-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Saville, S. P., Lazzell, A. L., Chaturvedi, A. K., Monteagudo, C., Lopez-Ribot, J. L. (2009). Efficacy of a Genetically Engineered Candida albicans tet-NRG1 Strain as an Experimental Live Attenuated Vaccine against Hematogenously Disseminated Candidiasis. CVI 16: 430-432 [Abstract] [Full Text]  
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