Diversity in polar lipid signatures and phenotypes of terbinafine susceptible and resistant clinical isolates of Trichophyton rubrum.

Terbinafine (TBF) remains a frontline therapeutic agent for dermatophytosis; however, resistance in Trichophyton rubrum is emerging as a significant clinical challenge. Here we present the mass spectrometry based lipidomic signatures of select clinical isolates of T.rubrum and draw attention to lipidomic changes related to TBF resistance. While there was no change in sterol content, an extensive lipid remodeling in PGL molecular species was observed. For example, a decreased unsaturation index, LPS/PS ratio, and LPA/PA ratio was observed in TBF resistant isolate. These changes were balanced by an increased odd fatty acyl containing and saturated -PGL molecular species, LPG/PG ratio, and LPI/PI ratio in TBF resistant isolate. Among SLs, PCer(t18:0/18:0(2OH)) species showed significant decrease in TBF resistant isolate. Additionally, decreased DAG and increased TAG contents point to the fact that lipid biosynthesis shifts from polar lipid synthesis towards TAG synthesis in the resistant isolate, while making necessary adjustments in PGL and SL molecular species to maintain membrane homeostasis and keep the sterol synthesis at optimum levels. Further, upon correlating the variations with phenotypes and enzymatic activities, a compensatory adaptation of stress in resistant isolates of T. rubrum is evident. Together, these datasets should be useful to understand the role of lipid homeostasis in the underlying mechanisms of TBF resistance and emphasize the potential lipid biosynthetic pathways to develop therapeutic interventions.