Echinocandin Resistance in Aspergillus fumigatus Has Broad Implications for Membrane Lipid Perturbations That Influence Drug-Target Interactions

Abstract

Echinocandin drugs target the fungal enzyme β-(1,3)-glucan synthase (GS), which is required for the synthesis of cell wall component β-(1,3)-d-glucan. They are first-line therapy for Candida infections but are increasingly used as second-line therapy for Aspergillus infections. Resistance to echinocandins has been mainly studied in Candida and occurs due to mutations in FKS genes encoding GS. In our recent report, we identified a novel mechanism of echinocandin resistance in Aspergillus fumigatus. We showed that caspofungin exposure modifies GS, rendering it insensitive to echinocandins. This mechanism of resistance involved alteration of the GS lipid microenvironment and was mediated via an off-target effect on mitochondria leading to increased reactive oxygen species (ROS). We hypothesized that caspofungin-induced ROS alters the lipid composition around GS, changing its conformation and making it insensitive to echinocandins. In this commentary, we review both fks1-dependent and fks1-independent mechanisms of echinocandin resistance in A fumigatus. We believe this new resistance mechanism is also conserved among Candida spp. with implications for drug tolerance and/or resistance. Furthermore, we propose that ROS acts as a signaling molecule regulating lipid biogenesis, which impacts the structure-function of membrane proteins with implications for other types of drug-target interactions.

Addressing Microbial Resistance Worldwide: Challenges over Controlling Life-Threatening Fungal Infections

“…Satish and Perlin (2019) proposed a model of echinocandin resistance in which no mutations in the fks1 gene were observed. In their study, in vitro exposure of A. fumigatus to caspofungin elicited mitochondrial reactive oxygen species production, resulting in alterations of the membrane lipid microenvironment of glucan synthase, which would lead to a decrease in the affinity between the enzyme and drug, contributing to the rise of a resistance phenotype in this fungus [ 104 ].…”

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

“…In case of pulmonary aspergillosis refractory to azoles, echinocandins, such as caspofungin or micafungin, or polyenes, such as amphotericin B, are used as second-line antifungal treatments ( 211 , 215 ). Echinocandins inhibit the synthesis of the fungal cell wall component β-(1,3)-D-glucan by targeting the β-(1,3)-glucan synthase ( 216 ). Little is known on the resistance mechanism to echinocandins in A. fumigatus , due to its limited use in the treatment of Aspergillosis ( 216 ).…”

“…Echinocandins inhibit the synthesis of the fungal cell wall component β-(1,3)-D-glucan by targeting the β-(1,3)-glucan synthase ( 216 ). Little is known on the resistance mechanism to echinocandins in A. fumigatus , due to its limited use in the treatment of Aspergillosis ( 216 ). Echinocandin resistance in A. fumigatus has been attributed to mutations in FKS genes encoding the β-(1,3)-glucan synthase ( 216 ).…”

“…Little is known on the resistance mechanism to echinocandins in A. fumigatus , due to its limited use in the treatment of Aspergillosis ( 216 ). Echinocandin resistance in A. fumigatus has been attributed to mutations in FKS genes encoding the β-(1,3)-glucan synthase ( 216 ). The same has been reported for C. albicans ( 217 ).…”

Novel Antifungal Agents and Their Activity against Aspergillus Species

“…Echinocandins also target the fungal cell wall by blocking β-1,3- d -glucan synthase, but SCY-078 is structurally distinct from the currently available echinocandins, constricting its effectiveness to echinocandin-resistant Aspergillus spp. [ 61 , 67 , 68 , 69 ].…”