Lathosterol oxidase (sterol C5-desaturase) deletion confers resistance to amphotericin B and sensitivity to acidic stress inLeishmania major

Abstract

8Lathosterol oxidase (LSO) catalyzes the formation of C5-C6 double bond in the synthesis 1 9 3 1 expression. Together, these findings suggest that the C5-C6 double bond is vital for the structure 3 2 of sterol core, and while the loss of LSO can lead to amphotericin B resistance, it also makes 3 3Leishmania parasites vulnerable to biologically relevant stress. 3 4 3 IMPORTANCE 3 5 Sterols are essential membrane components in eukaryotes and sterol synthesis inhibitors 3 6 can have potent effects against pathogenic fungi and trypanosomatids. Understanding the roles of 3 7 sterols will facilitate the development of new drugs and counter drug resistance. Lathosterol 3 8 oxidase (aka sterol C5-desaturase) is required for the formation of C5-C6 double bond in the 3 9 sterol core structure in mammals, fungi, protozoans, plants and algae. Functions of this C5-C6 4 0 double bond are not well understood. In this study, we generated and characterized a lathosterol 4 1 oxidase-null mutant in Leishmania major. Our data suggest that the C5-C6 double bond is vital 4 2 for the structure and membrane-stabilizing functions of leishmanial sterols. In addition, our 4 3 results imply that while mutations in lathosterol oxidase can confer resistance to amphotericin B, 4 4an important antifungal and antiprotozoal agent, the alteration in sterol structure leads to 4 5 significant defects in stress response that could be exploited for drug development. 4 6 4