Fig. 9: Proposed model highlighting the mechanistic basis of the azole resistance in the NCT complex.

The NCT complex is a global regulator, which acts as both a negative and a positive regulator of a wide range of gene regulation that includes secondary metabolism, cellular transport and sterol biosynthesis as important targets for virulence and azole resistance in A. fumigatus. The NCT complex fine-tunes expression of several genes in the ergosterol biosynthesis pathway and the azole efflux pump encoding cdr1 by directly interacting with their core promoter region. The NCT complex also acts as a key regulator of azole resistance by modulating the expression levels of the transcription factors associated with ergosterol biosynthesis and azole resistance; transcriptional repression of the activator-encoding srbA and atrR genes, and activation of the negative regulator-encoding hapC gene. Therefore, the loss of the NCT complex causes an increased level of cellular ergosterol content and an elevated production of Cdr1B that leads to a multi-drug-resistance phenotype to the azoles as well as the salvage therapeutics amphotericin B and terbinafine.