Adaptation of the emerging pathogenic yeast to high caspofungin concentrations correlates with cell wall changes.

has emerged as a fungal pathogen that causes nosocomial outbreaks worldwide. Diseases caused by this fungus are of concern, due to its reduced susceptibility to several antifungals. exhibits paradoxical growth (PG; defined as growth at high, but not intermediate antifungal concentrations) in the presence of caspofungin (CPF). We have characterized the cellular changes associated with adaptation to CPF. Using EUCAST AFST protocols, all isolates tested showed PG to CPF, although in some isolates it was more prominent. Most isolates also showed a trailing effect (TE) to micafungin and anidulafungin. We identified two genes in that encode the echinocandins target, namely β-1,3-glucan synthase. contained the consensus hot-spot (HS) 1 and HS2 sequences. only contained the HS1 region which had a change (F635Y), that has been shown to confer resistance to echinocandins in . PG has been characterized in other species, mainly , where high CPF concentrations induced an increase in chitin, cell volume and aggregation. In CPF only induced a slight accumulation of chitin, and none of the other phenomena. RNAseq experiments demonstrated that CPF induced the expression of genes encoding several GPI-anchored cell wall proteins, membrane proteins required for the stability of the cell wall, chitin synthase and mitogen-activated protein kinases (MAPKs) involved in cell integrity, such as and (). Our work highlights some of the processes induced in to adapt to echinocandins.