Activity of MGCD290, a Hos2 histone deacetylase inhibitor, in combination with azole antifungals against opportunistic fungal pathogens

Abstract

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, >or=0.5 but <4 for indifference, and >or=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 microg/ml) and was mostly active against azole-resistant yeasts, but the MICs against molds were high (16 to >32 microg/ml). MGCD290 was synergistic with fluconazole against 55 (60%) of the 91 isolates, with posaconazole against 46 (51%) of the 91 isolates, and with voriconazole against 48 (53%) of the 91 isolates. Synergy between fluconazole and MGCD290 was observed against 26/30 (87%) Candida isolates. All 23 of the 91 Candida isolates that were not fluconazole susceptible demonstrated a reduced fluconazole MIC that crossed an interpretive breakpoint (e.g., resistant [MIC, >or=64 microg/ml] to susceptible [MIC, <or=8 microg/ml]) when fluconazole was combined with MGCD290 at 0.12 to 4 microg/ml. The activity of fluconazole plus MGCD290 was also synergistic against 6/10 Aspergillus isolates. Posaconazole plus MGCD290 demonstrated synergy against 14/15 Zygomycetes (9 Rhizopus isolates and 5 Mucor isolates). Voriconazole plus MGCD290 demonstrated synergy against six of eight Fusarium isolates. Thus, MGCD290 demonstrated in vitro synergy with azoles against the majority of clinical isolates tested, including many azole-resistant isolates and genera inherently resistant to azoles (e.g., Mucor and Fusarium). Further evaluation of fungal HDAC inhibitor-azole combinations is indicated.