Effects of Antifungal Agents Alone and in Combination Against Candida glabrata Strains Susceptible or Resistant to Fluconazole

Alves, Izabel Almeida; Bandeira, Laíssa Arévalo; Mario, Débora Alves Nunes; Denardi, Laura Bedin; Neves, Louise Vignoles; Santúrio, Jânio Morais; Alves, Sydney Hartz

doi:10.1007/s11046-012-9538-7

Cited by 15 publications

(19 citation statements)

References 26 publications

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“…Orally administered 5FC represents an attractive alternative to azoles, although its use has diminished in recent years due to concerns regarding resistance and the related concern of toxicity associated with the high doses often used to counter resistance. 5FC-azole combination therapy would in theory reduce the likelihood of resistance to either agent, but previous studies observed, albeit inconsistently, that 5FC-azole combinations are antagonistic in C. glabrata (12,14,15,16). Here, we confirmed 5FC antagonism of azole activity and, furthermore, identified its likely mechanism.…”

Section: Discussionsupporting

confidence: 79%

“…Combinations are typically additive in their activity, or in some cases synergistic, providing further rationale for their use. For example, the combination 5FC-amphotericin B was reported to be synergistic versus C. glabrata (12). Since uptake is a major determinant of 5FC susceptibility (as evidenced by the resistance conferred by cytosine permease mutation), a likely explanation for this synergism is increased membrane permeability in amphotericin B-treated cells (13).…”

mentioning

confidence: 99%

“…Indeed, 5FC has been reported to antagonize the activity of three different azoles versus C. glabrata, including FLC and the imidazoles miconazole and ketoconazole (12,14,15). This antagonism argues against the clinical use of 5FC-azole combination therapy.…”

mentioning

confidence: 99%

“…On the other hand, only additive activity was reported for 5FC in combination with voriconazole and itraconazole (12,16). The basis for these different results is unclear.…”

mentioning

confidence: 99%

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Flucytosine Antagonism of Azole Activity versus Candida glabrata: Role of Transcription Factor Pdr1 and Multidrug Transporter Cdr1

Steier

Vermitsky

Toner

et al. 2013

Antimicrob Agents Chemother

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bInfections with the opportunistic yeast Candida glabrata have increased dramatically in recent years. Antifungal therapy of yeast infections commonly employs azoles, such as fluconazole (FLC), but C. glabrata frequently develops resistance to these inhibitors of ergosterol biosynthesis. The pyrimidine analog flucytosine (5-fluorocytosine [5FC]) is highly active versus C. glabrata but is now rarely used clinically due to similar concerns over resistance and, a related concern, the toxicity associated with high doses used to counter resistance. Azole-5FC combination therapy would potentially address these concerns; however, previous studies suggest that 5FC may antagonize azole activity versus C. glabrata. Here, we report that 5FC at subinhibitory concentrations antagonized the activity of FLC 4-to 16-fold versus 8 of 8 C. glabrata isolates tested. 5FC antagonized the activity of other azoles similarly but had only indifferent effects in combination with unrelated antifungals. Since azole resistance in C. glabrata results from transcription factor Pdr1-dependent upregulation of the multidrug transporter gene CDR1, we reasoned that 5FC antagonism might be similarly mediated. Indeed, 5FC-FLC antagonism was abrogated in pdr1⌬ and cdr1⌬ strains. In further support of this hypothesis, 5FC exposure induced CDR1 expression 6-fold, and this upregulation was Pdr1 dependent. In contrast to azoles, 5FC is not a Cdr1 substrate and so its activation of Pdr1 was unexpected. We observed, however, that 5FC exposure readily induced petite mutants, which exhibit Pdr1-dependent CDR1 upregulation. Thus, mitochondrial dysfunction resulting in Pdr1 activation is the likely basis for 5FC antagonism of azole activity versus C. glabrata.

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…On the other hand, only additive activity was reported for 5FC in combination with voriconazole and itraconazole (12,16). The basis for these different results is unclear.…”

mentioning

confidence: 99%

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Flucytosine Antagonism of Azole Activity versus Candida glabrata: Role of Transcription Factor Pdr1 and Multidrug Transporter Cdr1

Steier

Vermitsky

Toner

et al. 2013

Antimicrob Agents Chemother

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“…As mentioned above, echinocandins are effective antifungal agents against C. glabrata but resistance to these drugs is on the rise. Combined therapies have also been explored but unexpected complications have arisen in some cases (Alves et al, 2012). An oral drug that represents an alternative to azoles is 5-flurocytosine (5-FC), although there are concerns regarding resistance and toxicity associated with high doses used to negate resistance.…”

Section: Multidrug Resistance In C Glabratamentioning

confidence: 99%

Multidrug resistance in fungi: regulation of transporter-encoding gene expression

2014

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A critical risk to the continued success of antifungal chemotherapy is the acquisition of resistance; a risk exacerbated by the few classes of effective antifungal drugs. Predictably, as the use of these drugs increases in the clinic, more resistant organisms can be isolated from patients. A particularly problematic form of drug resistance that routinely emerges in the major fungal pathogens is known as multidrug resistance. Multidrug resistance refers to the simultaneous acquisition of tolerance to a range of drugs via a limited or even single genetic change. This review will focus on recent progress in understanding pathways of multidrug resistance in fungi including those of most medical relevance. Analyses of multidrug resistance in Saccharomyces cerevisiae have provided the most detailed outline of multidrug resistance in a eukaryotic microorganism. Multidrug resistant isolates of S. cerevisiae typically result from changes in the activity of a pair of related transcription factors that in turn elicit overproduction of several target genes. Chief among these is the ATP-binding cassette (ABC)-encoding gene PDR5. Interestingly, in the medically important Candida species, very similar pathways are involved in acquisition of multidrug resistance. In both C. albicans and C. glabrata, changes in the activity of transcriptional activator proteins elicits overproduction of a protein closely related to S. cerevisiae Pdr5 called Cdr1. The major filamentous fungal pathogen, Aspergillus fumigatus, was previously thought to acquire resistance to azole compounds (the principal antifungal drug class) via alterations in the azole drug target-encoding gene cyp51A. More recent data indicate that pathways in addition to changes in the cyp51A gene are important determinants in A. fumigatus azole resistance. We will discuss findings that suggest azole resistance in A. fumigatus and Candida species may share more mechanistic similarities than previously thought.

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Antifungal Activities of Diphenyl Diselenide alone and in Combination with Fluconazole or Amphotericin B against Candida glabrata

et al. 2013

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Here, we evaluated combinations of diphenyl diselenide [(PhSe)2] with fluconazole and amphotericin B in a checkerboard assay against clinical Candida glabrata strains. Minimal inhibitory concentration (geometric mean) ranged from 0.25 to >64 (5.16 μg/mL) for (PhSe)2, 1 to 32 (5.04 μg/mL) for fluconazole and 0.06 to 0.5 (0.18 μg/mL) for amphotericin B. Synergistic (76.66 %) and indifferent (23.34 %) interactions were observed for (PhSe)2 + amphotericin B combination. (PhSe)2 + fluconazole combination demonstrated indifferent (50 %) and antagonistic (40 %) interactions, whereas synergistic interactions were observed in 10 % of the isolates. New experimental in vivo protocols are necessary and will promote a better understanding of the antimicrobial activity of (PhSe)2 against C. glabrata and its use as an adjuvant therapy with antifungal agents.

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Effects of Antifungal Agents Alone and in Combination Against Candida glabrata Strains Susceptible or Resistant to Fluconazole

Cited by 15 publications

References 26 publications

Flucytosine Antagonism of Azole Activity versus Candida glabrata: Role of Transcription Factor Pdr1 and Multidrug Transporter Cdr1

Flucytosine Antagonism of Azole Activity versus Candida glabrata: Role of Transcription Factor Pdr1 and Multidrug Transporter Cdr1

Multidrug resistance in fungi: regulation of transporter-encoding gene expression

Antifungal Activities of Diphenyl Diselenide alone and in Combination with Fluconazole or Amphotericin B against Candida glabrata

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