Regulation of Ergosterol Biosynthesis in Pathogenic Fungi: Opportunities for Therapeutic Development

Abstract

Ergosterol plays a dual role in fungal pathogenesis and azole resistance, driving key advancements in the understanding of its biosynthesis regulation. This review integrates the latest research progress on the regulation of fungal ergosterol biosynthesis and its role in drug resistance and pathogenicity. We comprehensively discuss the functions of key enzymes (such as Erg11p/Cyp51A, Erg6p, Erg3p, and Erg25p) in the mevalonate, late, and alternative pathways. Notably, we highlight the complex regulation of cyp51A expression by factors such as SrbA, AtrR, CBC, HapX, and NCT in Aspergillus fumigatus, and elucidate the distinctive roles of Upc2, Adr1, and Rpn4 in Candida species. Importantly, we summarize recent discoveries on the CprA-dependent regulation of Cyp51A/Erg11p and heme-mediated stability control. Based on these findings, we propose innovative antifungal strategies, including dual-target inhibition and multi-enzyme inhibition by natural products, which provide novel insights and potential directions for the development of next-generation antifungal therapies.

Keywords: Aspergillus fumigatus; antimicrobial resistance; erg11A/cyp51A; ergosterol biosynthesis; pathogenic fungi.

Figure 1

The biosynthesis pathway of ergosterol in fungi. The diagram illustrates the key intermediates, final products, and enzymes involved in ergosterol synthesis. Different colors represent distinct modules, including the mevalonate pathway, late-stage ergosterol pathway, and alternative pathways.

Figure 2

Transcription factors involved in ergosterol biosynthesis in A. fumigatus. (A) The transcription factors SrbA, AtrR, and SltA function as positive regulators, promoting the expression of cyp51A. In contrast, the transcription factors NctA/NctB, the CCAAT-binding complex (CBC), and HapX serve as negative regulators, inhibiting cyp51A expression. (B) The NCT complex suppresses the expression of srbA, atrR, and erg11A while simultaneously activating hapC.

Figure 3

A diagram of potential roles of trans- and cis-acting factors at wild-type and TR34 cyp51A promoters. A hypothetical corepressor is pictured that makes multivalent contacts with the key regulators of cyp51A transcription. The proximal ATRE is indicated by a green hatched box. Other binding sites are color-coded with their respective regulators. Azole drugs trigger corepressor dissociation and gene activation. In the case of the TR34 promoter (right-hand diagrams), the distal SRE and ATRE in the upstream 34 bp repeat can bypass corepressor function and activate transcription. The 34 bp tandem repeats do not include the HXRE but maintain a CBC binding site. Interaction of the CBC with the adjacent HXRE is required for strong binding of these factors. Exposure of the TR34 cyp51A gene to azole drugs or loss of the pSRE or pATRE (shown here) triggers strong induction of expression. Adapted from Figure 2C in reference [42].

Figure 4

The transcription factors involved in ergosterol biosynthesis in Candida Species. The Upc2 transcription factor binds to ergosterol and remains inactive in the cytosol. Depletion of ergosterol changes Upc2 to an active form, which enters the nucleus and initiates the transcription of the genes for ergosterol biosynthesis. In C. albicans, activated Upc2 also triggers expression of the Adr1 transcription factor, which further leads to direct expression of ergosterol biosynthesis genes.