Elucidating the lactic acid tolerance mechanism in vaginal clinical isolates of Candida glabrata

Abstract

Abstract Incidence of vulvovaginal candidiasis are strikingly high and treatment options are limited with nearly 50% Candida glabrata cases left untreated or experience treatment failures. The vaginal microenvironment is rich in lactic acid (LA), and the adaptation of C. glabrata to LA is the main reason for clinical treatment failure. In the present study, C. glabrata and its vaginal clinical isolates were comprehensively investigated for their growth response, metabolic adaptation and altered cellular pathway to LA using different biochemical techniques, metabolic profiling and transcriptional studies. Candida glabrata shown considerable variations in its topological and biochemical features without compromizing growth in LA media. Chemical profiling data highlighted involvement of cell wall/membrane, ergosterol and oxidative stress related pathways in mediating adaptative response of C. glabrata towards LA. Furthermore, one dimensional proton (1H) NMR spectroscopy based metabolic profiling revealed significant modulation in 19 metabolites of C. glabrata cells upon growth in LA. Interestingly myo-inositol, xylose, putrescine, and betaine which are key metabolites for cell growth and viability were found to be differentially expressed by clinical isolates. These observations were supported by the transcriptional expression study of selected genes evidencing cell wall/membrane re-organization, altered oxidative stress, and reprogramming of carbon metabolic pathways. Collectively, the study advances our understanding on adaptative response of C. glabrata in vaginal microenvironment to LA for survival and virulence. Lay Summary In vaginal tract, LA present as a natural carbon source is a potentiating factor for vulvovaginal candidiasis caused by C. glabrata is highest. The present article delineates the lactic acid adaptation in vaginal clinical isolates of C. glabrata using a comprehensive approach of biochemical, metabolic, and transcriptional studies.