Increase of virulence and its phenotypic traits in drug-resistant strains of Candida albicans

Department of Public Health of Sciences "G. Sanarelli", University of Rome "La Sapienza", Italy; Department of Technology and Health, and Department of Infectious, Parasitic and Immunomediated Diseases. Istituto Superiore di Sanità, Rome, Italy; Istituto di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy

^* To whom correspondence should be addressed. Email: letizia.angiolella{at}uniroma1.it.

	Abstract

There is concern about the rise of antifungal drug resistance but little is known about comparative biological properties and pathogenicity of drug-resistant strains. We generated fluconazole (FLC; CO23_RFLC) or micafungin (FK; CO23_RFK)-resistant strains of Candida albicans by treating a FLC- and FK-susceptible strain of this fungus (CO23_S) with stepwise increasing concentrations of either drug. Molecular analyses showed that CO23_RFLC had acquired markedly increased expression of the drug-resistance MDR1 efflux pump MDR1 gene, whereas CO23_RFK had a homozygous mutation in the FSK1 gene. These genetic modifications did not alter to any extent the growth capacity of the drug-resistant strains, either at 28°C or at 37°C in vitro, but markedly increased their experimental pathogenicity in a systemic mouse infection model, as assessed by the overall mortality and target organ invasion. Interestingly, no apparent increase in the vaginopathic potential of the strains was observed in a oestrogen-dependent rat vaginal infection. The increased pathogenicity of drug-resistant strains for systemic infection was associated with a number of biochemical and physiological changes, inclusive of i) marked cellular alterations associated with a different expression and content of major cell wall polysaccharides; ii) more rapid and extensive hyphae formation both in liquid and solid media; iii) increased adherence to plastic and propensity for biofilm formation. Overall, our data demonstrate that experimentally-induced resistance to antifungal drugs, irrespective of drug family, can substantially divert C. albicans biology, particularly affecting biological properties of potential relevance for deep-seated candidiasis.