Escape of Candida from Caspofungin Inhibition at Concentrations above the MIC (Paradoxical Effect) Accomplished by Increased Cell Wall Chitin; Evidence for β-1,6-Glucan Synthesis Inhibition by Caspofungin

A reduction in β-1,6-glucan level has been reported in the literature for C. albicans during caspofungin treatment, along with an increase in the molecular size of β-1,6-glucan and cross-linking of glucan and chitin.

“In addition to the inhibition of the biosynthesis of the primary target, β-1,3-glucan, a reduction in β-1,6-glucan level has also been reported in the literature for C. albicans during caspofungin treatment80, along with an increase in the molecular size of β-1,6-glucan and cross-linking of glucan and chitin36.”

Induction of the CWI pathway in Candida species, including C. glabrata, has been linked to increased production of chitin, potentially compensating for loss of beta-1,3-glucans.

“Induction of the CWI pathway in Candida species (Stevens et al., 2006; Walker et al., 2013), including C. glabrata (Cota et al., 2008), has been linked to increased production of other cell wall components, such as chitin, potentially compensating for the loss of beta-1,3-glucans.”

Previous studies have linked the paradoxical effect with cell wall stress responses that permit growth in the presence of high concentrations of CAS, such as upregulation of chitin biosynthesis, high-osmolarity glycerol responses and calcium/calcineurin signalling pathways.

“Previous studies have linked the paradoxical effect with cell wall stress responses that permit growth in the presence of high concentration of CAS, such as upregulation of chitin biosynthesis, high-osmolarity glycerol responses and calcium/calcineurin signalling pathways [14].”