Glucose metabolic reprogramming and modulation in glycerol biosynthesis regulates drug resistance in clinical isolates ofCandida

Abstract

Aims The study is aimed at understanding the novel molecular mechanisms governing drug resistance in the opportunistic fungi belonging to the genus Candida. Methods and results This is a multipronged study wherein different assays like drug susceptibility and whole cell proteome analysis, stress tolerance assay, measurement of total internal glycerol content, western blot analysis, ROS measurement, glucose uptake, lactate production, ATP generation, and NADPH measurements were made. The study reveals an incidence of different species of Candida in the northern most part of India (Kashmir valley). Resistant isolates, mostly resistant to azoles were reported across all the species. The study revealed a difference in resistance mechanisms between C. albicans and C. glabrata clinical isolates. Further, such resistance mechanism (in the case of C. albicans) was mostly mediated by Hexokinase 2 (Hxk2) and Glucose-6-phosphate dehydrogenase (G6pd). Increased expression of Hxk2 was associated with increased glucose uptake, more lactate production, and more ATP generation in drug-resistant C. albicans. At the same time, increased G6pd expression was responsible for the increased production of NADPH, which imparts a better ROS scavenging potential. While in C. glabrata the resistance was linked with glycerol metabolism, where the drug-resistant isolate tends to accumulate more glycerol as an osmolyte in response to external stresses. This glycerol accumulation was found to be triggered by the HOG1-MAPK pathway. Conclusion The study concludes that, like various human malignant tumors, there is a strong correlation between drug resistance and aberrant cellular metabolism in the opportunistic fungi belonging to the genus Candida.

Multi-Omics Profiling of Candida albicans Grown on Solid Versus Liquid Media

“…The proteome of C. albicans has been extensively described elsewhere [40][41][42][43][44]. To our knowledge, there have not been any direct comparisons made between the proteome or metabolome of C. albicans (or other pathogenic fungi) in liquid cell culture versus solid media.…”

“…Recently, multi-omics analysis has made a major contribution to the field of medical microbiology [35][36][37][38], specifically liquid chromatography-mass spectrometry-based, and proteomics/metabolomics approaches have provided the research community with key molecular and cellular elements that provide a comprehensive understanding of microbial system biology and important aspects of microbial physiology [35,36,39]. Of note, until now, most of the multi-omics studies performed on C. albicans were performed in liquid media, which has been, beyond any doubt, a valuable contribution to this research field (e.g., [40][41][42][43][44]). However, there are well-known limitations in performing proteomics/metabolomics analysis in liquid medium.…”