INK128 Exhibits Synergy with Azoles againstExophialaspp. andFusariumspp.
Infections ofExophialaspp. andFusariumspp. 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 thein vitroactivities of INK128 alone and the interactions of INK128 with conventional antifungal drugs including itraconazole, voriconazole, posaconazole, and amphotericin B against 18 strains ofExophialaspp. and 10 strains ofFusariumspp. 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%Exophialastrains and 60%Fusariumstrains, despiteFusariumstrains exhibited high MIC values (4-8 μg/ml) against voriconazole. In addition, synergistic effects of INK128/itraconazole were shown in 33%Exophialastrains and 30%Fusariumstrains, while synergy of INK128/posaconazole were observed in 28%Exophialastrains and 30%Fusariumstrains. The effective working ranges of INK128 were 0.125-2 μg/ml and 1-4 μg/ml againstExophialaisolates andFusariumisolates, 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 thein vitroantifungal activity of voriconazole, itraconazole and posaconazole againstExophialaspp. andFusariumspp., suggesting that azoles, especially voriconazole, combined with TOR kinase inhibitor might provide a potential strategy to the treatment ofExophialaandFusariuminfections. However, further investigations are warranted to elucidate the underlying mechanism and to determine possible reliable and safe application in clinical practice.
Department of Dermatology, Zhongshan Hospital Fudan University Shanghai, China.
Lujuan
L
Gao
Department of Dermatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University Jingzhou, China.
Yi
Y
Sun
The Second Clinical Medical College, Yangtze University Jingzhou, China.
Chengyan
C
He
Department of Dermatology, Zhongshan Hospital Fudan University Shanghai, China.
Ming
M
Li
Department of Dermatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University Jingzhou, China.
Tongxiang
T
Zeng
Department of Dermatology, Central Hospital of Xiangyang (Affiliated Hospital of Hubei College of Arts and Sciences) Xiangyang, China.
Qiaoyun
Q
Lu
Exophiala; Fusarium; INK128; TOR inhitibor; itraconazole; posaconazole; synergy; voriconazole