Art. 1.1320

European Review for Medical and Pharmacological Sciences
Fluconazole resistance in Candida albicans:
a review of mechanisms
I.A. CASALINUOVO, P. DI FRANCESCO, E. GARACI Department of Experimental Medicine and Biochemical Sciences, Microbiology University of Rome “Tor Vergata” – Rome (Italy) A b s t r a c t . – Antifungal agents have
Resistance to azole antifungals was reported greatly contributed to the improvement of pub-
in the late 1980s in C. albicans after prolonged lic health. Nevertheless, antifungal resistant
therapy with miconazole and ketoconazole.
pathogens have increased during the past
Fluconazole is a bis-triazole discovered in decade, becoming a serious concern. Candida
the 1990s. This compound has been shown to albicans has been the most extensively stud-
ied pathogen in antifungal resistance because
possess potent antifungal activity against of their morbidity and mortality associated
with infections in immunocompromised pa-
such as C. immitis, H. capsulatum, B. dermati- tients. This review describes the antifungal
tidis, P. brasiliensis and S. schenckii1.
mechanims of the azole fluconazole widely
In spite of its widespread use in the med- used for the prophylaxis and treatment of can-
ical community, many reports described the didal infections. The specific molecular path-
clinical failure of fluconazole therapy in indi- ways occurring in fluconazole-resistance of C.
albicans and some issues about new antifun-
gal agents are also discussed.
Recently, fluconazole-resistant C. albicans strains and intrinsically resistant Candida species such as C. glabrata and C. krusei are Fluconazole, Candida albicans, Ergosterol, Antifungal treated for therapy or prophylaxis5-8.
These and other data have led to research on the molecular mechanisms operating toconfer fluconazole resistance.
In this article we review the current knowl- edge on the principal resistance mechanisms Introduction
to fluconazole (Table I). In addition, otherpotential explanations resulting from new ex- In recent years, fungal infections have in- perimental data about the above-mentioned mechanisms are discussed. The findings have lead to a new therapeutic approach in the prevention or control of Candida infections.
mune disease and organ or tissue transplan-tion. Candida albicans, a commensal fungusof the oral cavity and gastrointestinal tractin humans, represents one the major causes Fluconazole
of mucosal infection and systemic infection,which can be life threatening if not treated.
into imidazoles and triazoles (Figure 1).
(azoles, allylamines and morpholines), di- mazole and ketoconazole) consist of a five- membered ring structure containing two ni- (polyenes) or target cell wall biosynthesis trogen atoms with a complex side chain at- tached to one of the nitrogen atoms.
I.A. Casalinuovo, P. Di Francesco, E. Garaci Table I. Overview of fluconazole resistance mechanisms in C. albicans.
Molecular basis of
Final change accounting
References
fluconazole resistance
for resistance
Reduced drug affinity for the target enzyme aAllelic differences elimination by gene conversion or mitotic recombination lead to identical mutations in two al-leles; the resulting phenotype is significantly more resistant.
bCDRs genes are associated with cross-resistance to other azoles.
Miconazole
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Figure 1. Chemical structures of azole antifungal agents.
Fluconazole resistance in Candida albicans: a review of mechanisms Fluconazole and itraconazole are triazole compounds containing an additional nitrogen rhoea, hepatotoxicity, have rarely been re- in the ring9. Other antifungals of new genera- tion such as posaconazole, ravuconazole and Prophylactic administration of fluconazole voriconazole, also belong to triazoles.
has been reserved for selected patients con- The azole compounds inhibit the lanosterol sidered to be at high risk of candidemia13. In demethylase enzyme (or 14α-sterol demethy- particular, invasive fungal infections have be- lase); this enzyme converts lanosterol to er- come increasingly prevalent in individuals from lanosterol. The 14α-sterol demethylase neutropenic patients, HIV-infected patients and transplant recipients. The agreement for the fluconazole-prophylaxis is still controver- heme moiety in its active site. The azoles sial14. However, there is a general consensus bind to the heme iron through an unhindered that resistant strains are related to drug expo- nitrogen, thus inhibiting the enzymatic reac- tion. In addition, a second nitrogen of the Fluconazole is fungistatic; this makes it azoles interacts directly with the apoprotein clear that host factors contribute to the out- of lanosterol-demethylase. It is thought that the affinity of different azoles for the enzymeis also determined by the position of this sec-ond nitrogen10-12.
ERG11 and Other ERG Genes
fungal plasma membranes; it is important formembrane integrity and for the activity of The inhibition of 14α-sterol demethylase leads to the accumulation of 14α-methylated demethylase, an essential enzyme for ergos- sterols, resulting in a defective cell membrane terol synthesis. Resistance to azole antifungal with decreased availability of ergosterol and drugs has been associated with ERG11 gene overexpression and/or point mutations and also alterations in the ergosterol biosynthetic cholesterol. However, the azoles used in ther- apeutic concentrations demonstrate greater lanosterol 14α-demethylase and results in in- affinity for fungal P-450 demethylase than for the mammalian enzyme. Fluconazole appears whelms the capacity of the antifungal drug.
to be free of adverse effects on steroid hor- The effect of ERG11 gene overexpression on mone production1 and it is available in both antifungal susceptibility has been described intravenous and oral formulations. Because by several studies in C. albicans15-17 and also of the low toxicity and ready distribution into in C. glabrata and C. dubliniensis clinical iso- aqueous body fluids such as cerebrospinal fluid (CSF), fluconazole has been used in the treatment of both superficial and systemic in C. albicans as a consequence of azoles ex- posure was observed in matched sets of clini- cal isolates from the same strain20,21. In vitro discovered in the early 1950s), a favourable demonstrated in additional Candida species pharmacokinetic profile (metabolic stability, such as C. tropicalis, C. glabrata and C. water solubility) and availability as an oral and parenteral formulation. These factors Recently, in an analysis of unmatched sets have contributed to its therapeutic use in of clinical isolates it was found that resistance both normal and immunocompromised hosts.
zole therapy such as nausea, headache, skin that depletion of the ERG11 gene in C. I.A. Casalinuovo, P. Di Francesco, E. Garaci glabrata results in the accumulation of 4,14- merase was associated with fluconazole resis- demethylzimosterol, which did not cause de- tance22,34,35. In contrast, other studies found fective growth of fungal cells in vitro and in that the ERG1 gene was repressed in resis- has also been associated with point mutations was observed first in S. cerevisiae43. Defective of the ERG11 gene25-27; these mutations re- sterol C5,6-desaturase was attributed as the sult in conformational changes that reduce ef- cause of fluconazole resistance in C. albicans fective binding between azoles and their tar- clinical isolates from AIDS patients44. Such isolates accumulated ergosterol precursors in- Several investigators found sequence dif- ferences of the ERG11 gene in fluconazole- dienol. The molecular mechanisms associated resistant C. albicans and in S. cerevisiae with ERG3 defects are still unclear45,46.
transformants28-30. A list of differentaminoacid exchanges has been provided bydifferent studies that could simply reflect al-lelic variations31. In fluconazole-resistant C. Expression of Two Major
albicans isolates frequently observed nu- Efflux Pumps
cleotide changes were concerned with twoaminoacids located near the heme binding site (R467K [arginine 467 replaced by lysine] and G464S [glycine 464 replaced by serine]); this probably resulted in structural or func- tional alterations reducing fluconazole affini- The correlation between decreased suscep- porters operate through a proton gradient.
tibility to azole drugs and nucleotide changes CDR2 (Candida Drug Resistance), as well as that encoding a major facilitator, CaMDR1 Recently, other nucleotide substitutions in ERG11 gene were identified (K143R [lysine have been shown to be overexpressed47-51 in 143 replaced by arginine], E266D [glutamic C. albicans azole-resistant isolates. CaMDR1 acid 266 replaced by aspartic acid], V404L is specific for fluconazole resistance but not [valine 404 replaced by leucine], V488I [va- for other azoles48. Upregulation of these ef- line 488 replaced by isoleucine]) in three C. flux pumps reduces the effective concentra- albicans isolates33; these mutations were asso- tions of fluconazole in the fungal cell and is ciated with the fluconazole resistance pheno- correlated to azole resistance in C. albicans.
type. As suggested by investigators, a single Genetic deletion of the CDR1 gene resulted aminoacid change, not interacting with the in hypersusceptibility to azole drugs52, where- active site of ERG11p, was unrelated to drug as CDR2 gene disruption did not cause hy- resistance. Moreover, mesh membrane struc- persusceptibility to these agents. The latter ture developments were observed in the en- gene is closely related to CDR1 and disrup- doplasmic reticula of resistant cells33.
Several molecular and genetic studies have creased hypersusceptibility to azole antifun- described other ERG genes involved in the complex ergosterol biosynthesis as alterna- tive pathways, which were more or less corre- ed with benomyl resistance in S. cerevisiae) lated to fluconazole exposure: ERG1, ERG2, gene deletion in resistant strains of C. albi- cans does not result in increased susceptibili- In C. albicans, increased expression of through CDR4) correlated with increased re- sistance to fluconazole, ketoconazole and Fluconazole resistance in Candida albicans: a review of mechanisms itraconazole37. This resistance, however, Some of the C. albicans cell wall glycopro- arose rapidly after fluconazole exposure and teins have been found to be highly immuno- was transient. In fact, susceptibility resulted genic and differently modulated according to in azole-free media and also in vivo after the drug was no longer administered to the pa- In vitro studies on the cell wall of flucona- zole-susceptible and -resistant C. albicans To date, the molecular mechanisms involv- strains detected altered distribution of cell wall glucan-associated proteins63. These re- CaMDR) have not yet been elucidated.
sults suggest that fluconazole treatment could Recently, it has been shown that Cdr1p and have an effect on fungal cell wall metabolism and structure63,64, and these effects may be CDR2 genes) in C. albicans act as phospho- stably incorporated into the cell wall upon ac- lipids translocators eliciting in-to-out transbi- The asexual and diploid nature of C. albi- membrane. It is interesting that fluconazole cans65,66 complicates the characterization of could inhibit this transbilayer movement54.
gene expression in antifungal drug resistance.
Several studies investigating changes in chro- mosome copy number, loss (or not) of het- Recent results show that in vitro acquired erozygosity, gene disruption at definite loci resistance to fluconazole of C. albicans and other genetic strategies have been linked strains was associated with variation in mem- to fluconazole resistance67-70. These studies brane lipid fluidity and asymmetry56.
show that other factors may contribute to flu- conazole resistance development. However, a differences in gene expression identified new detailed analysis of these and other promising genes associated or not with drug resistance in C. albicans. Several of these genes werecoordinately regulated with both CDR genesand CaMDR1, whereas others appeared notto be coordinately regulated with known re- Different Targets and New
sistance genes35,36. These data suggest that Therapeutic Approaches
the efflux pumps may be regulated by com-bined expression of several genes. Analysis of these differentially regulated genes re- regulatory patterns and new antifungal treat- quires further investigation and opens up the ments are currently being undertaken.
possibility of finding new targets for antifun- pathway and modulation of the susceptibilityto antifungal azoles have been examined. C.
albicans mutants in the genes encoding theproteins responsible for cAMP synthesis Other Changes in Fluconazole
Resistance
fluconazole and other sterol biosynthesis in-hibitors71. The addition of cAMP conferred Recently, antifungal resistance results in partial-to-complete reversal of this hypersus- biofilm-associated infections57-59. Efflux ceptibility. These data suggest that antifungal pumps do not appear to contribute to flu- susceptibility could be modulated by adeny- conazole resistance in C. albicans at late (in- termediate and mature) stages in biofilm for- mation60, but solely in the early-phase. On (CsA) and tacrolimus hydrate (FK506, a 23- the contrary, changes in sterol profile were member macrolide) are promising candidates expressed by resistant phenotypes at interme- for antifungal therapy, due to their synergis- diate and mature phases. Therefore, phase- tic fungicidal effect in combination with specific mechanisms are suggested to be op- azoles and non-azole antifungal agents72,73.
erative in antifungal resistance of biofilm Cyclosporine has several cellular targets in- I.A. Casalinuovo, P. Di Francesco, E. Garaci transporters and the cyclophilin-calmodulin- 5) CASE CP, MACGOWAN AP, BROWN NM, REEVES DS, calcineurin pathway. The mechanism of this WHITEHEAD P, FELMINGHAM D. Prophylactic oral flu-conazole and candida fungaemia. Lancet 1991; fungicidal synergism is unknown and was re- cently reported not to be involved with mul-tidrug efflux transporters74.
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Acknowledgments
75) DI FRANCESCO P, GAZIANO R, CASALINUOVO IA, et al.
We thank Emanuele Rodolà for his excellent tech- Combined effect of fluconazole and thymosin al- nical assistance. This work was supported by MI- pha 1 on systemic candidiasis in mice immuno-suppressed by morphine treatments. Clin Exp UR, 60% and progetto FIRB n° RBNE01P4B5-

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