Increase of Virulence and Its Phenotypic Traits in Drug-Resistant Strains of Candida albicans

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 efflux pump encoded by the 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 in vitro, either at 28°C or at 37°C, 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 with an estrogen-dependent rat vaginal infection. The increased pathogenicity of drug-resistant strains for systemic infection was associated with a number of biochemical and physiological changes, including (i) marked cellular alterations associated with a different expression and content of major cell wall polysaccharides, (ii) more rapid and extensive hypha formation in both liquid and solid media, and (iii) increased adherence to plastic and a 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, affecting in particular biological properties of potential relevance for deep-seated candidiasis.

Quercetin Sensitizes Fluconazole-Resistant Candida albicans To Induce Apoptotic Cell Death by Modulating Quorum Sensing

“…5B and C). Farnesol can also affect the expression of virulence factors such as phospholipase, proteinase, esterase, and hemolysin, which are reported to facilitate the proliferation and pathogenicity of C. albicans (14). Further, SD agar medium supplemented with different amounts of QC and incubated for 5 days showed inhibition of phospholipase, proteinase, and esterase activities (Fig.…”

“…Fluconazole (FCZ) is most widely used to treat candidiasis infections because of its high bioavailability and low toxicity (11)(12)(13). However, excessive and indiscriminate clinical use of FCZ has led to the emergence of multiple-drug-resistant (MDR) strains of C. albicans (5,14,15). Importantly, these MDR strains occur at frequencies higher than mutation rates and, consistent with this, seem to be genetically identical to the drug-sensitive microbe.…”

Fluconazole Assists Berberine To Kill Fluconazole-Resistant Candida albicans

“…Fluconazole (FLC) is most widely used due to its high bioavailability and low toxicity (5,6). However, with the increasing clinical use of FLC, drug-resistant isolates are emerging rapidly (7)(8)(9)(10)(11). The high mortality rate of invasive Candida infections and limited availability of highly effective antifungal agents make it necessary to develop new antifungal therapeutics.…”

Reliability of the Vitek 2 Yeast Susceptibility Test for Detection of In Vitro Resistance to Fluconazole and Voriconazole in Clinical Isolates of Candida albicans and Candida glabrata

“…In cases of discrepant results, testing of both methods (the Vitek 2 system and reference BMD) were repeated and the results for the second runs were accepted as the final results. Expression of the CDR1, CDR2, SNQ2, and ERG11 genes from C. glabrata isolates and of the CDR1, CDR2, MDR1, and ERG11 genes from C. albicans isolates was quantitatively assessed with real-time reverse transcription-PCR in an i-Cycler iQ system (Bio-Rad Laboratories, Hercules, CA), using primers, probes, and thermal conditions described previously (2,27,29). For relative quantification of the target genes, each set of primer pairs and the TaqMan probe were used in combination with the primers and probe specific for the ACT1 (29) or TEF3 (2) gene in separate reactions.…”