Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro

Abstract

Cryptococcus neoformans infections in patients with AIDS are often incurable, despite aggressive antifungal therapy. Combination regimens with additive or synergistic drugs could provide additional options for treating cryptococcal meningitis. We evaluated the efficacy of combination therapies using L-743,872, a pneumocandin antifungal drug, and amphotericin B or fluconazole against 18 strains of C. neoformans, including 11 C. neoformans var. neoformans, 3 C. neoformans var. gattii, and 4 fluconazole-resistant isolates. The combination of subinhibitory concentrations of L-743,872 with amphotericin B significantly enhanced amphotericin B activity against C. neoformans as measured by turbidity (antifungal susceptibility studies using the National Committee of Clinical and Laboratory Standards method), quantitative CFU, and tetrazolium salt reduction assays. Similarly, the addition of subinhibitory concentrations of L-743,872 to fluconazole enhanced fluconazole activity, but the effect was less dramatic than for the pneumocandin-amphotericin B combination. A marked synergism was observed in all combinations of amphotericin B and L-743, 872 (fractional inhibitory concentration index [FIC] of < or = 0.5). Fluconazole-resistant strains showed a susceptibility to amphotericin B and L-743,872 which was comparable to that of susceptible isolates. Combinations of pneumocandin with fluconazole revealed different activities for the various strains, including synergism (FIC < 1.0), additivity (FIC = 1.0), and autonomy (FIC between 1.0 and 2.0). Combination studies with fluconazole and L-743,872 showed additive and autonomous activities against fluconazole-resistant isolates. No antagonistic interactions (FIC < 2.0) were observed for any combination of L-743,872 with either amphotericin B or fluconazole. The results of this study suggest that L-743,872 can enhance the efficacy of fluconazole or amphotericin B in vitro and indicate a potential role for L-743,872 in combination therapy against C. neoformans.

Vacuolar H+-ATPase plays a key role in cell wall biosynthesis of Aspergillus niger

“…To address the question if a proper V-ATPase function is required for the regulation of the CWI pathway in A. niger, we cultured the parental strain and the conditional mutant in CM medium for 12 h and subsequently treated the mycelium with caspofungin or bafilomycinB 1 for 1 h. Caspofungin has been shown to be a potent inhibitor of the b-1,3-glucan synthesis in yeast as well as in filamentous fungi (Franzot and Casadevall, 1997;Meyer et al, 2007) causing the induction of the CWI-pathway, including induced expression of genes encoding cell wall protein and cell wall remodeling enzymes. BafiloymcinB 1 a known inhibitor of the V-ATPases, has been shown to reduce the radial growth rate and to induce morphological changes in fungi (Melin et al, 1999).…”

Serotonin (5-HT) enhances the activity of amphotericin B against Aspergillus fumigatus in vitro

“…The suspension was further diluted in RPMI 1640 medium to obtain (0.2-1.2) × 10 5 cfu/mL. Combination testing was performed by the chequerboard method as previously described [11]. Serial twofold dilutions of each drug stock solution were prepared at four times the strength of the final drug concentration.…”

Synergistic action of amphotericin B and rhamnolipid in combination on Candida parapsilosis and Trichosporon cutaneum

“…1), which show the synergistic effect of the simultaneous use of rhamnolipid and amphotericin B for planktonic cells (FICi = 0.5). Several studies suggest a threshold for synergistic effect at FICi B 1.0 (Franzot and Casadevall 1997;Yu et al 1984); in more recent publications, this threshold is set at FICi B 0.5 (Kumar et al 2015).…”