FIG 8.
A putative working model for sltA-mediated itraconazole resistance. SltA directly binds to the conserved AGGCA motif to contribute to azole resistance via regulating the expression of the drug target Erg11A and the drug transporter Mdr1 in A. fumigatus, and this binding is dependent on the conserved cysteine and histidine within the C2H2 DNA binding domain. The cysteine and histidine were mutated to Ser and Ala, respectively, which are marked with stars. Under itraconazole conditions, sltA is induced at the mRNA level. SltA transcriptionally regulates drug transporters (Mdr1, AbcE, and MfsC) to extrude excess intracellular itraconazole. On the other hand, SltA transcriptionally regulates ergosterol biosynthetic enzymes (Erg11A, Erg13A, and Erg24A) to withstand itraconazole and is involved in the biosynthesis of ergosterol under itraconazole conditions.