Journal of Antimicrobial Chemotherapy (2001) 48, 75-81
© 2001 The British Society for Antimicrobial Chemotherapy
Resistance to itraconazole in Aspergillus nidulans and Aspergillus fumigatus is conferred by extra copies of the A. nidulans P-450 14
-demethylase gene, pdmA
a Division of Pathology and Laboratory Medicine, and b Department of Internal Medicine Specialties, Section of Infectious Diseases, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
Triazoles selectively inhibit the cytochrome P-450-dependent C-14 lanosterol 
-demethylase (P-450 14 DM), a key enzyme in ergosterol biosynthesis in fungi. To investigate mechanisms of triazole resistance in a mould, we used Aspergillus nidulans, a genetically amenable model fungus closely related to more pathogenic members of the genus. We selected for genes that would give resistance to itraconazole following transformation with a high copy genomic library of A. nidulans. In all the resistant colonies that we isolated, resistance was conferred by extra copies of the A. nidulans P-450 14 DM gene, pdmA. We determined that in A. nidulans, extra copies of pdmA increase the MIC for itraconazole 36 times over wild-type controls. Similarly, transformation of an Aspergillus fumigatus strain with pITZR1 resulted in increased resistance to itraconazole. Our results indicate that triazole resistance in clinical isolates of moulds may result from amplification or overexpression of the P-450 14 DM and demonstrate the utility of A. nidulans as a promising model fungus for the analysis of drug resistance and susceptibility in the pathogenic fungus A. fumigatus.
* Corresponding author. Tel: +1-713-745-1945; Fax: +1-713-792-4840; E-mail: gsmay{at}mdanderson.org
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Pinchai, B. Z. Perfect, P. R. Juvvadi, J. R. Fortwendel, R. A. Cramer Jr., Y. G. Asfaw, J. Heitman, J. R. Perfect, and W. J. Steinbach Aspergillus fumigatus Calcipressin CbpA Is Involved in Hyphal Growth and Calcium Homeostasis Eukaryot. Cell, April 1, 2009; 8(4): 511 - 519. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Cramer Jr., B. Z. Perfect, N. Pinchai, S. Park, D. S. Perlin, Y. G. Asfaw, J. Heitman, J. R. Perfect, and W. J. Steinbach Calcineurin Target CrzA Regulates Conidial Germination, Hyphal Growth, and Pathogenesis of Aspergillus fumigatus Eukaryot. Cell, July 1, 2008; 7(7): 1085 - 1097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Cowen and W. J. Steinbach Stress, Drugs, and Evolution: the Role of Cellular Signaling in Fungal Drug Resistance Eukaryot. Cell, May 1, 2008; 7(5): 747 - 764. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ma, J. Qiao, W. Liu, Z. Wan, X. Wang, R. Calderone, and R. Li The Sho1 Sensor Regulates Growth, Morphology, and Oxidant Adaptation in Aspergillus fumigatus but Is Not Essential for Development of Invasive Pulmonary Aspergillosis Infect. Immun., April 1, 2008; 76(4): 1695 - 1701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Mellado, G. Garcia-Effron, L. Alcazar-Fuoli, W. J. G. Melchers, P. E. Verweij, M. Cuenca-Estrella, and J. L. Rodriguez-Tudela A New Aspergillus fumigatus Resistance Mechanism Conferring In Vitro Cross-Resistance to Azole Antifungals Involves a Combination of cyp51A Alterations Antimicrob. Agents Chemother., June 1, 2007; 51(6): 1897 - 1904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Reyes, A. Romans, C. K. Nguyen, and G. S. May Novel Mitogen-Activated Protein Kinase MpkC of Aspergillus fumigatus Is Required for Utilization of Polyalcohol Sugars Eukaryot. Cell, November 1, 2006; 5(11): 1934 - 1940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Romano, G. Nimrod, N. Ben-Tal, Y. Shadkchan, K. Baruch, H. Sharon, and N. Osherov Disruption of the Aspergillus fumigatus ECM33 homologue results in rapid conidial germination, antifungal resistance and hypervirulence Microbiology, July 1, 2006; 152(7): 1919 - 1928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Steinbach, R. A. Cramer Jr., B. Z. Perfect, Y. G. Asfaw, T. C. Sauer, L. K. Najvar, W. R. Kirkpatrick, T. F. Patterson, D. K. Benjamin Jr., J. Heitman, et al. Calcineurin Controls Growth, Morphology, and Pathogenicity in Aspergillus fumigatus. Eukaryot. Cell, July 1, 2006; 5(7): 1091 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. da Silva Ferreira, J. L. Capellaro, E. dos Reis Marques, I. Malavazi, D. Perlin, S. Park, J. B. Anderson, A. L. Colombo, B. A. Arthington-Skaggs, M. H. S. Goldman, et al. In Vitro Evolution of Itraconazole Resistance in Aspergillus fumigatus Involves Multiple Mechanisms of Resistance Antimicrob. Agents Chemother., November 1, 2004; 48(11): 4405 - 4413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liu, G. S. May, M. S. Lionakis, R. E. Lewis, and D. P. Kontoyiannis Extra Copies of the Aspergillus fumigatus Squalene Epoxidase Gene Confer Resistance to Terbinafine: Genetic Approach to Studying Gene Dose-Dependent Resistance to Antifungals in A. fumigatus Antimicrob. Agents Chemother., July 1, 2004; 48(7): 2490 - 2496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Mellado, G. Garcia-Effron, L. Alcazar-Fuoli, M. Cuenca-Estrella, and J. L. Rodriguez-Tudela Substitutions at Methionine 220 in the 14{alpha}-Sterol Demethylase (Cyp51A) of Aspergillus fumigatus Are Responsible for Resistance In Vitro to Azole Antifungal Drugs Antimicrob. Agents Chemother., July 1, 2004; 48(7): 2747 - 2750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Nascimento, G. H. Goldman, S. Park, S. A. E. Marras, G. Delmas, U. Oza, K. Lolans, M. N. Dudley, P. A. Mann, and D. S. Perlin Multiple Resistance Mechanisms among Aspergillus fumigatus Mutants with High-Level Resistance to Itraconazole Antimicrob. Agents Chemother., May 1, 2003; 47(5): 1719 - 1726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Barker, M. M. Pearson, and P. D. Rogers Identification of genes differentially expressed in association with reduced azole susceptibility in Saccharomyces cerevisiae J. Antimicrob. Chemother., May 1, 2003; 51(5): 1131 - 1140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Diaz-Guerra, E. Mellado, M. Cuenca-Estrella, and J. L. Rodriguez-Tudela A Point Mutation in the 14{alpha}-Sterol Demethylase Gene cyp51A Contributes to Itraconazole Resistance in Aspergillus fumigatus Antimicrob. Agents Chemother., March 1, 2003; 47(3): 1120 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Mann, R. M. Parmegiani, S.-Q. Wei, C. A. Mendrick, X. Li, D. Loebenberg, B. DiDomenico, R. S. Hare, S. S. Walker, and P. M. McNicholas Mutations in Aspergillus fumigatus Resulting in Reduced Susceptibility to Posaconazole Appear To Be Restricted to a Single Amino Acid in the Cytochrome P450 14{alpha}-Demethylase Antimicrob. Agents Chemother., February 1, 2003; 47(2): 577 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E. Verweij, D. T. A. Te Dorsthorst, A. J. M. M. Rijs, H. G. De Vries-Hospers, and J. F. G. M. Meis Nationwide Survey of In Vitro Activities of Itraconazole and Voriconazole against Clinical Aspergillus fumigatus Isolates Cultured between 1945 and 1998 J. Clin. Microbiol., July 1, 2002; 40(7): 2648 - 2650. [Abstract] [Full Text] [PDF]
|
|