Recent insights into the mechanisms of antifungal resistance
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The incidence of fungal infections has increased in recent years, particularly among immunocompromised individuals. Treatment of invasive fungal infections has been hampered by a limited number of available antifungal agents and both intrinsic and acquired resistance to these agents among many fungal pathogens. Therefore, much interest has focused on elucidating the molecular basis for antifungal resistance. Recent efforts have increased our understanding of this process, including the transcriptional regulation of azole resistance in Candida spp, mechanisms of intrinsic resistance to amphotericin B, and mechanisms of acquired resistance to the new echinocandin class of antifungal agents. This review discusses these and other newly clarified resistance mechanisms, as well as the direction of future antifungal resistance research. Despite these advances, undiscovered resistance determinants exist, and resistance to newer agents likely will continue to emerge.
- Young LY, Hull CM, Heitman J: Disruption of ergosterol biosynthesis confers resistance to amphotericin B in Candida lusitaniae. Antimicrob Agents Chemother 2003, 47:2717–2724. CrossRef
- Kelly SL, Lamb DC, Kelly DE, et al.: Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol delta5,6-desaturation. FEBS Lett 1997, 400:80–82. CrossRef
- Nolte FS, Parkinson T, Falconer DJ, et al.: Isolation and characterization of fluconazole- and amphotericin B-resistant Candida albicans from blood of two patients with leukemia. Antimicrob Agents Chemother 1997, 41:196–199.
- Sanglard D, Ischer F, Parkinson T, et al.: Candida albicans mutations in the ergosterol biosynthetic pathway and resistance to several antifungal agents. Antimicrob Agents Chemother 2003, 47:2404–2412. CrossRef
- Barker KS, Crisp S, Wiederhold N, et al.: Genome-wide expression profiling reveals genes associated with amphotericin B and fiuconazole resistance in experimentally induced antifungal resistant isolates of Candida albicans. J Antimicrob Chemother 2004, 54:376–385. CrossRef
- Vermes A, Guchelaar HJ, Dankert J: Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 2000, 46:171–179. CrossRef
- Hope WW, Tabernero L, Denning DW, Anderson MJ:Molecular mechanisms of primary resistance to flucytosine in Candida albicans. Antimicrob Agents Chemother 2004, 48:4377–4386. CrossRef
- Bennett JE: Antimicrobial agents: Antifungal Agents. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics, edn 10. Edited by Hardman JG and Limbird LE. New York: McGraw-Hill; 2001:1295–1312.
- Dodgson AR, Dodgson KJ, Pujol C, et al.: Clade-specific flucytosine resistance is due to a single nucleotide change in the FUR1 gene of Candida albicans. Antimicrob Agents Chemother 2004, 48:2223–2227. An important study that groups C. albicans strains into clades and demonstrates that flucytosine resistance in this Candida spp is associated with clade categorization. CrossRef
- Chapeland-Leclerc F, Bouchoux J, Goumar A, et al.: Inactivation of the FCY2 gene encoding purine-cytosine permease promotes cross-resistance to flucytosine and fluconazole in Candida lusitaniae. Antimicrob Agents Chemother 2005, 49:3101–3108. CrossRef
- Lopez-Ribot JL, McAtee RK, Lee LN, et al.: Distinct patterns of gene expression associated with development of fluconazole resistance in serial Candida albicans isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob Agents Chemother 1998, 42:2932–2937.
- White TC, Marr KA, Bowden RA: Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev 1998, 11:382–402.
- Morschhäuser J: The genetic basis of fluconazole resistance development in Candida albicans. Biochim Biophys Acta 2002, 1587:240–248.
- Ruhnke M, Eigler A, Tennagen I, et al.: Emergence of fluconazole-resistant strains of Candida albicans in patients with recurrent oropharyngeal candidosis and human immunodeficiency virus infection. J Clin Microbiol 1994, 32:2092–2098.
- Sanglard D, Ischer F, Calabrese D, et al.: The ATP binding cassette transporter gene CgCDR1 from Candida glabrata is involved in the resistance of clinical isolates to azole antifungal agents. Antimicrob Agents Chemother 1999, 43:2753–2765.
- Bennett JE, Izumikawa K, Marr KA: Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob Agents Chemother 2004, 48:1773–1777. CrossRef
- Redding SW, Kirkpatrick WR, Saville S, et al.: Multiple patterns of resistance to fluconazole in Candida glabrata isolates from a patient with oropharyngeal candidiasis receiving head and neck radiation. J Clin Microbiol 2003, 41:619–622. CrossRef
- Hahn RC, Morato Conceicao YT, Santos NL, et al.:Disseminated paracoccidioidomycosis: correlation between clinical and in vitro resistance to ketoconazole and trimethoprim sulphamethoxazole. Mycoses 2003, 46:342–347. CrossRef
- Wheat LJ, Connolly P, Smedema M, et al.: Emergence of resistance to fluconazole as a cause of failure during treatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome. Clin Infect Dis 2001, 33:1910–1913. CrossRef
- Dannaoui E, Borel E, Monier MF, et al.: Acquired itraconazole resistance in Aspergillus fumigatus. J Antimicrob Chemother 2001, 47:333–340. CrossRef
- Akins R: An update on antifungal targets and mechanisms of resistance in Candida albicans. Med Mycol 2005, 43:285–318. CrossRef
- Niimi M, Niimi K, Takano Y, et al.:Regulated overexpression of CDR1 in Candida albicans confers multidrug resistance. J Antimicrob Chemother 2004, 54:999–1006. CrossRef
- Hiller D, Sanglard D, Morschhäuser J: Overexpression of the MDR1 gene is sufficient to confer increased resistance to toxic compounds in Candida albicans. Antimicrob Agents Chemother 2006, 50:1365–1371. CrossRef
- Rogers PD, Barker KS: Genome-wide expression proflle analysis reveals coordinately regulated genes associated with stepwise acquisition of azole resistance in Candida albicans. Antimicrob Agents Chemother 2003, 47:1220–1227. The first report of a Candida-specific microarray used to directly compare gene expression profiles of susceptible and resistant isolates from a matched set of clinical isolates. It demonstrated the utility of this technology to find genes co-regulated with known resistance genes or genes otherwise associated with azole resistance. CrossRef
- Hooshdaran MZ, Barker KS, Hilliard GM, et al.: Proteomic analysis of azole resistance in Candida albicans clinical isolates. Antimicrob Agents Chemother 2004, 48:2733–2735. CrossRef
- Kusch H, Biswas K, Schwanfelder S, et al.: A proteomic approach to understanding the development of multidrugresistant Candida albicans strains. Mol Genet Genomics 2004, 271:554–565. CrossRef
- Wirsching S, Michel S, Kohler G, Morschhäuser J:Activation of the multiple drug resistance gene MDR1 in fluconazole-resistant, clinical Candida albicans strains is caused by mutations in a trans-regulatory factor. J Bacteriol 2000, 182:400–404. CrossRef
- de Micheli M, Bille J, Schueller C, Sanglard D: A common drug-responsive element mediates the upregulation of the Candida albicans ABC transporters CDR1 and CDR2, two genes involved in antifungal drug resistance. Mol Microbiol 2002, 43:1197–1214. CrossRef
- Coste AT, Karababa M, Ischer F, et al.: TAC1, Transcriptional Activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2. Eukaryot Cell 2004, 3:1639–1652. The characterization of the transcription factor that regulates a major factor in C. albicans resistance to azole antifungals: the CDR genes. CrossRef
- Coste A, Turner V, Ischer F, et al.: A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics 2006, 172:2139–56. CrossRef
- Saidane S, Weber S, De Deken X, et al.: PDR16-mediated azole resistance in Candida albicans. Mol Microbiol 2006, 60:1546–1562. CrossRef
- Harry JB, Oliver BG, Song JL, et al.: Drug-induced regulation of the MDR1 promoter in Candida albicans. Antimicrob Agents Chemother 2005, 49:2785–2792. CrossRef
- Hiller D, Stahl S, Morschhäuser J: Multiple cis-acting sequences mediate upregulation of the MDR1 efflux pump in a fluconazole-resistant clinical Candida albicans isolate. Antimicrobial Agents Chemother 2006, 50:2300–2308. CrossRef
- Agarwal AK, Rogers PD, Baerson SR, et al.: Genome-wide expression profiling of the response to polyene, pyrimidine, azole, and echinocandin antifungal agents in Saccharomyces cerevisiae. J Biol Chem 2003, 278:34998–35015. CrossRef
- MacPherson S, Akache B, Weber S, et al.: Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes. Antimicrob Agents Chemother 2005, 49:1745–1752. CrossRef
- Silver PM, Oliver BG, White TC: Role of Candida albicans transcription factor Upc2p in drug resistance and sterol metabolism. Eukaryot Cell 2004, 3:1391–1397. CrossRef
- Vermitsky JP, Edlind TD: Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob Agents Chemother 2004, 48:3773–3781. CrossRef
- Tsai HF, Krol AA, Sarti KE, Bennett JE: Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob Agents Chemother 2006, 50:1384–1392. This report and [39 ] are the first to definitively determine that the Pdr1p transcription factor is the regulator of CDR1 in C. glabrata. CrossRef
- Vermitsky JP, Earhart KD, Smith WL, et al.: Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol 2006, 61:704–722. This report and [38 ] are the first to definitively determine that the Pdr1p transcription factor is the regulator of CDR1 in C. glabrata. This report employs microarray analysis to give a more complete understanding of PDR1 transcriptional regulation. CrossRef
- Wirsching S, Moran GP, Sullivan DJ, et al.: MDR1-mediated drug resistance in Candida dubliniensis. Antimicrob Agents Chemother 2001, 45:3416–3421. CrossRef
- Pinjon E, Moran GP, Jackson CJ, et al.: Molecular mechanisms of itraconazole resistance in Candida dubliniensis. Antimicrob Agents Chemother 2003, 47:2424–2437. CrossRef
- Perea S, Lopez-Ribot JL, Wickes BL, et al.: Molecular mechanisms of fluconazole resistance in Candida dubliniensis isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob Agents Chemother 2002, 46:1695–1703. CrossRef
- Hernandez S, Lopez-Ribot JL, Najvar LK, et al.: Caspofungin resistance in Candida albicans: correlating clinical outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient with progressive Candida esophagitis. Antimicrob Agents Chemother 2004, 48:1382–1383. The first report that reports on caspofungin resistance in C. albicans developing in a clinical setting. This case report also determined that caspofungin MICs correlated with clinical outcomes and tissue burden in a mouse in vivo model. CrossRef
- Krogh-Madsen M, Arendrup MC, Heslet L, Knudsen JD:Amphotericin B and caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient. Clin Infect Dis 2006, 42:938–944. CrossRef
- Park S, Kelly R, Kahn JN, et al.: Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother 2005, 49:3264–3273. This report characterizes the amino acid substitutions in Fks1p from C. albicans that account for reduced susceptibility to caspofungin and introduced a mutant allele of FKS1 into a susceptible isolate resulting in reduced caspofungin susceptibility. CrossRef
- Schuetzer-Muehlbauer M, Willinger B, Krapf G, et al.: The Candida albicans Cdr2p ATP-binding cassette (ABC) transporter confers resistance to caspofungin. Mol Microbiol 2003, 48:225–235. CrossRef
- Niimi K, Maki K, Ikeda F, et al.: Overexpression of Candida albicans CDR1, CDR2, or MDR1 does not produce significant changes in echinocandin susceptibility. Antimicrob Agents Chemother 2006, 50:1148–1155. CrossRef
- Recent insights into the mechanisms of antifungal resistance
Current Infectious Disease Reports
Volume 8, Issue 6 , pp 449-456
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