Recent advances and challenges in the treatment of invasive fungal infections

Shao, Pei-Lan; Huang, Li‐Min; Hsueh, Po-Ren

doi:10.1016/j.ijantimicag.2007.07.019

Cited by 110 publications

(67 citation statements)

References 99 publications

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“…The number of antifungal families available and their use in therapy is very limited (1)(2)(3)(4). Recently, a new family of specific fungal cell wall synthesis inhibitors has emerged as an alternative antifungal therapy and is gaining increasing relevance yearly (5)(6)(7).…”

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confidence: 99%

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Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

Martins¹,

Cortés²,

Muñoz³

et al. 2011

Journal of Biological Chemistry

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Three specific ␤(1,3)glucan synthase (GS) inhibitor families, papulacandins, acidic terpenoids, and echinocandins, have been analyzed in Schizosaccharomyces pombe wild-type and papulacandin-resistant cells and GS activities. Papulacandin and enfumafungin produced similar in vivo effects, different from that of echinocandins. Also, papulacandin was the strongest in vitro GS inhibitor (IC 50 10 3 -10 4 -fold lower than with enfumafungin or pneumocandin), but caspofungin was by far the most efficient antifungal because of the following. 1) It was the only drug that affected resistant cells (minimal inhibitory concentration close to that of the wild type). 2) It was a strong inhibitor of wild-type GS (IC 50 close to that of papulacandin). 3) It was the best inhibitor of mutant GS. Moreover, caspofungin showed a special effect for two GS inhibition activities, of high and low affinity, separated by 2 log orders, with no increase in inhibition. pbr1-8 and pbr1-6 resistances are due to single substitutions in the essential Bgs4 GS, located close to the resistance hot spot 1 region described in Saccharomyces and Candida Fks mutants. Bgs4 pbr1-8 contains the E700V change, four residues N-terminal from hot spot 1 defining a larger resistance hot spot 1-1 of 13 amino acids. Bgs4 pbr1-6 contains the W760S substitution, defining a new resistance hot spot 1-2. We observed spontaneous revertants of the spherical pbr1-6 phenotype and found that an additional A914V change is involved in the recovery of the wild-type cell shape, but it maintains the resistance phenotype. A better understanding of the mechanism of action of the antifungals available should help to improve their activity and to identify new antifungal targets.

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“…These inhibitors include echinocandins (lipopeptides), papulacandins (glycolipids), and acidic terpenoids such as enfumafungin (2,11). To date, only the echinocandins caspofungin, micafungin, and anidulafungin have been approved (in years 2002,2005, and 2006, respectively) for treatment of invasive fungal infections (1,3,5,7,12).…”

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confidence: 99%

Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

Martins¹,

Cortés²,

Muñoz³

et al. 2011

Journal of Biological Chemistry

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“…andida species represent an important cause of nosocomial infections with high morbidity and mortality rates (28,33). Over the past few years, epidemiological changes have been registered: the incidence of C. albicans has been reduced followed by a growing incidence of non-albicans species (9,21,34).…”

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Novel Method for Evaluating In Vitro Activity of Anidulafungin in Combination with Amphotericin B or Azoles

et al. 2012

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A combination of drugs possessing different targets has been used as salvage therapy, although without scientific support. In vitro studies validating such combinations are scarce, and the methodology is very laborious and time-consuming. This study proposes a flow cytometric (FC) protocol as an alternative to evaluate the effect of the combination of anidulafungin (AND) with amphotericin B (AMB) and azoles (fluconazole and voriconazole), tested upon 39 and 36 Candida strains, respectively. The concentration assayed in the combination was 0.5× MIC of each drug. The membrane potential marker DiBAC 4 (3) [Bis-(1,3-dibutylbarbituric acid) trimethine oxonol] was used for AND-AMB, and the metabolic marker FUN-1 was used for AND-azoles. Drug interaction was determined by calculating a staining index (SI): the sum of the percentage of depolarized cells (DC) after treatment with drug combinations divided by the DC of the drug alone, and the sum of the mean intensity of fluorescence (MIF) displayed by cells treated with drug combinations divided by the MIF of the drug alone for FUN-1. An SI of <1 means antagonism, an SI between 1 and 4 means no interaction, and an SI of >4 means synergism. The combination of AND and AMB by FC and checkerboard was synergistic for 46 and 43% of isolates and antagonistic for 5 and 8%, respectively. For the combination of AND and azoles, it was synergistic for 36% and antagonistic for 3% by FC and synergistic for 44% and antagonistic for 3% by checkerboard. When the FC method was compared to the gold standard checkerboard method, the agreement was 0.91 (95% confidence interval [95% CI] of 0.88 to 0.94), sensitivity was 0.88 (95% CI of 0.73 to 0.95), and specificity was 0.95 (95% CI of 0.84 to 1). Thus, FC is a rapid and reliable method (<2 h) to assess the effect of antifungal combinations.

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“…At present, the azole class of antifungal agents constitutes one of the cornerstones of therapy for opportunistic mycoses due to many yeasts and molds (3,16,20,24,28,30,31,33). Unfortunately, the clinical efficacy of this class of agents may be compromised by intrinsic or acquired resistance (11,25,27,30).…”

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Activity of MGCD290, a Hos2 Histone Deacetylase Inhibitor, in Combination with Azole Antifungals against Opportunistic Fungal Pathogens

Pfaller¹,

Messer²,

et al. 2009

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We report on the in vitro activity of the Hos2 fungal histone deacetylase (HDAC) inhibitor MGCD290 (MethylGene, Inc.) in combination with azoles against azole-resistant yeasts and molds. Susceptibility testing was performed by the CLSI M27-A3 and M38-A2 broth microdilution methods. Testing of the combinations (MGCD290 in combination with fluconazole, posaconazole, or voriconazole) was performed by the checkerboard method. The fractional inhibitory concentrations were determined and were defined as <0.5 for synergy, >0.5 but <4 for indifference, and >4 for antagonism. Ninety-one isolates were tested, as follows: 30 Candida isolates, 10 Aspergillus isolates, 15 isolates of the Zygomycetes order, 10 Cryptococcus neoformans isolates, 8 Rhodotorula isolates, 8 Fusarium isolates, 5 Trichosporon isolates, and 5 Scedosporium isolates. MGCD290 showed modest activity when it was used alone (MICs, 1 to 8 g/ml) and was mostly active against azoleresistant yeasts, but the MICs against molds were high (16 to >32 g/ml).

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Recent advances and challenges in the treatment of invasive fungal infections

Cited by 110 publications

References 99 publications

Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

Novel Method for Evaluating In Vitro Activity of Anidulafungin in Combination with Amphotericin B or Azoles

Activity of MGCD290, a Hos2 Histone Deacetylase Inhibitor, in Combination with Azole Antifungals against Opportunistic Fungal Pathogens

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