Octyl gallate reduce ABC multidrug transporter CaCdr1p expression and lead to its mislocalization in azole-resistant clinical isolates of Candida albicans.
J Glob Antimicrob Resist. 2020 Apr 25;:
Authors: Singh S, Fatima Z, Hameed S
OBJECTIVES: Fungal pathogens pose a serious threat to public health. Widespread and prolonged usage of antifungal drugs has led to multidrug resistance (MDR) development in human fungal pathogen, Candida albicans. Among several mechanisms governing drug resistance in C. albicans, overexpression of drug efflux transporters by far remains the leading cause of MDR facilitated by overexpression of ATP Binding Cassette (ABC) or major facilitator superfamily (MFS) transporters. Hence targeting efflux pumps still represents a promising approach. In this study we analyzed the effect of octyl gallate (OG), a natural food additive, on drug efflux pump activity of C. albicans.
METHODS: Drug efflux pump activity was estimated by rhodamine 6G efflux (R6G) and nile red accumulation assay with Candida drug resistance protein 1 (CaCdr1p) over expressing strain. Gene and protein expression along with localization was studied by RT-PCR, Western blot and confocal microscopy. Ergosterol content was measured by alcoholic KOH method.
RESULTS: OG specifically inhibits CaCdr1p activity belonging to ABC superfamily. Underlying mechanism confirmed competitive mode of inhibition by OG as revealed by Lineweaver-Burk plot. Furthermore, OG leads to reduced expressions ofCDR1, CaCdr1p and causes mislocalization respectively. Additionally, OG sensitizes azole sensitive and resistant clinical matched pair of isolates Gu4/Gu5 and led to impeded R6G efflux and depleted ergosterol content.
CONCLUSION: OG being a potent inhibitor of CaCdr1p that chemosensitizes drug resistant C. albicans warrants further studies to be exploited as an effective antifungal agent.
PMID: 32344123 [PubMed - as supplied by publisher]