Cellular energy status is indispensable for perillyl alcohol mediated abrogated membrane transport in Candida albicans

The prevalence of fungal infections and their resistance patterns in fungal isolates from large number of patients with impaired immunity still remains poorly monitored. In spite of significant advances being made in the improvement of antifungal drugs, only a limited number of antifungal drugs are currently available. The present study aimed to gain further mechanistic insights into the previously described anticandidal activity of natural monoterpenoid, perillyl alcohol (PA). We found that cellular transport across cell membrane was abrogated in presence of PA. This was demonstrated by dose and time dependent enhanced cellular leakage accompanied by inhibited sodium and potassium cellular transport. In addition, we found disrupted pH homeostasis which was depicted by enhanced extracellular pH. We further observed that mitochondrial energy status is highly integrated with the antifungal activity of PA. This was evident from inhibited propidium iodide (PI) uptake in presence of sodium azide and di-nitro phenol (DNP) which showed no fluorescence when treated with PA. Moreover, we observed that PA leads to disrupted mitochondrial membrane potential. Additional cell death hallmarks in response to PA such as nuclear fragmentation was also observed with 4',6-diamidino-2-phenylindole (DAPI) staining. Taken together, PA is a novel candidate that deserves further attention to be exploited as effective antifungal agent of pharmacological interest.