The Elevated Endogenous Reactive Oxygen Species Contribute to the Sensitivity of the Amphotericin B-Resistant Isolate of Aspergillus flavus to Triazoles and Echinocandins

Abstract

Aspergillus flavus has been frequently reported as the second cause of invasive aspergillosis (IA), as well as the leading cause in certain tropical countries. Amphotericin B (AMB) is a clinically important therapy option for a range of invasive fungal infections including invasive aspergillosis, and in vitro resistance to AMB was associated with poor outcomes in IA patients treated with AMB. Compared with the AMB-susceptible isolates of A. terreus, the AMB-resistant isolates of A. terreus showed a lower level of AMB-induced endogenous reactive oxygen species (ROS), which was an important cause of AMB resistance. In this study, we obtained one AMB-resistant isolate of A. flavus, with an AMB MIC of 32 μg/mL, which was sensitive to triazoles and echinocandins. This isolate presented elevated endogenous ROS levels, which strongly suggested that no contribution of decreased AMB-induced endogenous ROS for AMB-resistance, opposite to those observed in A. terreus. Further, we confirmed that the elevated endogenous ROS contributed to the sensitivity of the AMB-resistant A. flavus isolate to triazoles and echinocandins. Further investigation is needed to elucidate the causes of elevated endogenous ROS and the resistance mechanism to AMB in A. flavus.

Recent Advances in Fungal Infections: From Lung Ecology to Therapeutic Strategies With a Focus on Aspergillus spp.

“…The same has been reported for C. albicans ( 217 ). Amphotericin B (AmB) has been shown to bind to ergosterol in the fungal cell membrane and form pores, thus disrupting the cell membrane integrity ( 218 , 219 ). AmB has also been reported to induce endogenous production of ROS leading to oxidative stress and fungal death ( 219 ).…”

“…Amphotericin B (AmB) has been shown to bind to ergosterol in the fungal cell membrane and form pores, thus disrupting the cell membrane integrity ( 218 , 219 ). AmB has also been reported to induce endogenous production of ROS leading to oxidative stress and fungal death ( 219 ). Although resistance to AmB is rare, A. terreus has been shown to be intrinsically resistant ( 218 ).…”