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Expression of the CDR1 efflux pump in clinical Candida albicans isolates is controlled by a negative regulatory

Naseem Akhtar Gaur1, Raman Manoharlal, Preeti Saini

  • 1Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

Biochemical and Biophysical Research Communications
|May 18, 2005
PubMed

Insights

A negative regulatory element (NRE) in the Candida albicans CDR1 gene normally keeps its expression low. In drug-resistant strains, this NRE is less active, leading to high CDR1 expression and azole resistance.

Area of Science:

  • Medical Mycology
  • Molecular Biology
  • Antimicrobial Resistance

Background:

  • Azole antifungal drug resistance in Candida albicans is a significant clinical challenge.
  • This resistance is frequently linked to the overexpression of the CDR1 gene, encoding an ABC transporter efflux pump.
  • The role of regulatory elements within the CDR1 promoter in clinical resistance is not fully understood.

Purpose of the Study:

  • To investigate the functional significance of a negative regulatory element (NRE) in the CDR1 promoter.
  • To determine the NRE's role in controlling CDR1 expression in clinical isolates of Candida albicans.
  • To elucidate the NRE's involvement in azole drug resistance.

Main Methods:

  • Utilized reporter gene assays (GFP and lacZ) to measure CDR1 promoter activity.
  • Generated and analyzed strains with mutations or deletions in the CDR1 promoter's NRE.
  • Employed electrophoretic mobility shift assays (EMSA) to assess NRE-DNA binding by nuclear factors.

Main Results:

  • CDR1 promoter activity was significantly higher in azole-resistant C. albicans isolates compared to azole-sensitive isolates.
  • Deletion or mutation of the NRE increased reporter gene expression in sensitive strains but not in resistant strains.
  • EMSA revealed reduced binding of nuclear factors to the NRE in resistant isolates compared to sensitive isolates.

Conclusions:

  • The NRE actively represses CDR1 gene expression, maintaining basal levels.
  • This repression is diminished or overcome in azole-resistant clinical isolates of C. albicans.
  • Dysfunctional NRE contributes to constitutive CDR1 overexpression and azole drug resistance in Candida albicans.

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