Multidrug Resistance

Multidrug resistance (MDR)  is typically defined as the ability of a living cell to show resistance to a wide variety of structurally and functionally unrelated compounds. In mammals, tumours, which are initially sensitive to cytotoxic agents, often develop resistance to a broad spectrum of structurally unrelated drugs. The widespread occurrence of MDR in tumour cells represents a major impediment to successful cancer chemotherapy. Cultured cell lines resistant to multiple drugs express increased levels of a 170 kDa membrane glycoprotein named P-glycoprotein (P-gp) encoded by MDR1 . It is an ATP-dependent extrusion pump for drugs and physiological substrates.

Resistance to antifungals evolves slowly during the course of chemotherapy. Studies so far suggest that antifungal resistance in Candida is a multifactor phenomenon. The primary mechanisms include alterations in ergosterol biosynthetic pathway by the over expression of ERG11 which encodes the drug target enzyme 14a-lanosterol demethylase or by an alteration (point mutations) in target enzymes which leads to reduced affinity to fluconazole. Reduced intracellular accumulation of drugs is another prominent mechanism of resistance in Candida wherein drug extrusion pumps belonging to ABC ( ATP binding cassette) and MFS (Major Facilitator) super families  of proteins are over expressed. We and others have demonstrated that genes encoding ABC or MFS proteins are over expressed in azole resistant clinical isolates of C.albicans   Furthermore; Candida cells which show enhanced expression of efflux pumps encoding genes also show simultaneous increase in the efflux of drugs thereby directly linking the pump activity with cell’s ability to confer antifungal resistance. Efflux of incoming drug prevents cells to accumulate lethal concentration of azoles and enable them to survive.  Interestingly, drug inactivation that is very common in bacteria has not been observed in Candida cells. Recent studies on transcriptional profiling of sensitive versus resistant clinical isolates and that in presence or absence of azoles are revealing even more complexities in multi-drug resistance.

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