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Antimicrobial Agents and Chemotherapy, April 2002, p. 1046-1052, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.1046-1052.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro Low-Level Resistance to Azoles in Candida albicans Is Associated with Changes in Membrane Lipid Fluidity and Asymmetry

Avmeet Kohli,1 NFN Smriti,1 Kasturi Mukhopadhyay,1 Ashok Rattan,2 and Rajendra Prasad1*

Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University,1 Microbiology Division, Ranbaxy Research Laboratories, New Delhi, India2

Received 9 May 2001/ Returned for modification 10 August 2001/ Accepted 12 December 2001

The present study tracks the development of low-level azole resistance in in vitro fluconazole-adapted strains of Candida albicans, which were obtained by serially passaging a fluconazole-susceptible dose-dependent strain, YO1-16 (fluconazole MIC, 16 µg ml-1) in increasing concentrations of fluconazole, resulting in strains YO1-32 (fluconazole MIC, 32 µg ml-1) and YO1-64 (MIC, 64 µg ml-1). We show that acquired resistance to fluconazole in this series of isolates is not a random process but is a gradually evolved complex phenomenon that involves multiple changes, which included the overexpression of ABC transporter genes, e.g., CDR1 and CDR2, and the azole target enzyme, ERG11. The sequential rise in fluconazole MICs in these isolates was also accompanied by cross-resistance to other azoles and terbinafine. Interestingly, fluorescent polarization measurements performed by using the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene revealed that there was a gradual increase in membrane fluidity of adapted strains. The increase in fluidity was reflected by observed change in membrane order, which was considerably decreased (decrease in fluorescence polarization values, P value) in the adapted strain (P value of 0.1 in YO1-64, compared to 0.19 in the YO1-16 strain). The phospholipid composition of the adapted strain was not significantly altered; however, ergosterol content was reduced in YO1-64 from that in the YO1-16 strain. The asymmetrical distribution of phosphatidylethanolamine (PE) between two monolayers of plasma membrane was also changed, with PE becoming more exposed to the outer monolayer in the YO1-64 strain. The results of the present study suggest for the first time that changes in the status of membrane lipid phase and asymmetry could contribute to azole resistance in C. albicans.

* Corresponding author. Mailing address: School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India. Phone: 91-11-6107676, ext. 2509. Fax: 91-11-6165886. E-mail: rp47{at}hotmail.com.

Antimicrobial Agents and Chemotherapy, April 2002, p. 1046-1052, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.1046-1052.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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