INK128 Exhibits Synergy with Azoles against spp. and spp.

Infections of spp. and spp. are often chronic and recalcitrant. Systemic disseminations, which mostly occur in immunocompromised patients, are often refractory to available antifungal therapies. The conserved target of rapamycin (TOR) orchestrates cell growth and proliferation in response to nutrients and growth factors, which are important for pathogenicity and virulence. INK128 is a second-generation ATP-competitive TOR inhibitor, which binds the TOR catalytic domain and selectively inhibits TOR. In the present study, we investigated the activities of INK128 alone and the interactions of INK128 with conventional antifungal drugs including itraconazole, voriconazole, posaconazole, and amphotericin B against 18 strains of spp. and 10 strains of spp. via broth microdilution checkerboard technique system adapted from Clinical and Laboratory Standards Institute broth microdilution method M38-A2. INK128 alone was inactive against all isolates tested. However, favorable synergistic effects between INK128 and voriconazole were observed in 61% strains and 60% strains, despite strains exhibited high MIC values (4-8 μg/ml) against voriconazole. In addition, synergistic effects of INK128/itraconazole were shown in 33% strains and 30% strains, while synergy of INK128/posaconazole were observed in 28% strains and 30% strains. The effective working ranges of INK128 were 0.125-2 μg/ml and 1-4 μg/ml against isolates and isolates, respectively. No synergistic effect was observed when INK128 was combined with amphotericin B. No antagonism was observed in all combinations. In conclusion, INK128 could enhance the antifungal activity of voriconazole, itraconazole and posaconazole against spp. and spp., suggesting that azoles, especially voriconazole, combined with TOR kinase inhibitor might provide a potential strategy to the treatment of and infections. However, further investigations are warranted to elucidate the underlying mechanism and to determine possible reliable and safe application in clinical practice.