Original Article

The Journal of Antibiotics (2007) 60, 436–446; doi:10.1038/ja.2007.56

The Mechanism of Overcoming Multidrug Resistance (MDR) of Fungi by Amphotericin B and Its Derivatives

Magdalena lisz1, Barbara Cybulska1, Jolanta Grzybowska1, Jacek Czub1, Rajendra Prasad2 and Edward Borowski1

  1. 1Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, 11/12, Narutowicza St, 80-952 Gdansk, Poland
  2. 2School of Life Sciences, Javaharlal Nehru University, New Delhi, India

Correspondence: E. Borowski, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, 11/12, Narutowicza St, 80-952 Gdansk, Poland. E-mail: borowski@.chem.pg.gda.pl

Received 12 December 2006; Accepted 6 July 2007.

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Abstract

Comparative studies were performed to determine the activity and cytotoxicity of amphotericin B (AmB) and its derivatives on standard strain of Saccharomyces cerevisiae and its transformants with cloned genes from Candida albicans encoding multidrug resistance (MDR) pumps of ATP-binding cassette and major facilitator superfamilies. The AmB derivatives: amphotericin B 3-dimethylaminopropyl amide and N-methyl-N-D-fructopyranosylamphotericin B methyl ester were shown to be fungistatic and fungicidal towards MDR strains, by membrane permeabilization mechanism. Antibiotic-cell interaction monitored by energy transfer method indicates similar membrane affinity in parent strain and its MDR transformants. Experiments with fungal cells loaded with rhodamine 6G point to lack of competition between this dye and AmB and its derivatives for efflux driven by CDR2p. It can be thus assumed that AmB and its derivatives overcome fungal MDR by not being substrates of the multidrug exporting pumps, presumably due to their large molecular volumes.

Keywords:

amphotericin B, amphotericin B derivatives, antifungal activity, multidrug resistance