The Fungal CYP51s: Their Functions, Structures, Related Drug Resistance, and Inhibitors

Conclusion and Perspectives CYP51 plays a crucial role in fungal invasive growth, hyphae formation and virulence, and inhibitors targeting CYP51 have always been an important component of antifungal agents. Further researches on fungal CYP51s might set about from the following aspects: First, while the detailed crystal structures of several susceptible pathogenic fungi CYP51 have been elaborated, those of drug-resistant variants are still in hypothesis. If those structures were elucidated, targeting at common drug-resistant CYP51 protein variants could probably be promising. Second, it deserves more in-depth researches to find out why some kind of amino acid point mutations (such as G54W in A. fumigatus CYP51A) could have varied effects on resistance for different azoles. Such researches may provide important ideas to minimize drug resistance. Third, the study of model organisms may also bring some inspiration. Such as Set4, which targets to ergosterol gene promoters with a Hap1-dependent manner under hypoxic conditions in S. cerevisiae, could downregulates the expression of CYP51. Whether homologous proteins and similar mechanisms exist in pathogenic fungi requires further researches. As long as they exist, new remedies may be put forward to activate Set4 to inhibit azole-induced CYP51 overexpression. Forth, it might be achievable to target other proteins as well as CYP51 simultaneously to maximize the therapeutic effect. There already exists some preliminary works focusing...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research