Analysis of physico-chemical properties of substrates of ABC and MFS multidrug transporters of pathogenic Candida albicans

Puri, Nidhi; Prakash, Om; Manoharlal, Raman; Sharma, Monika; Ghosh, Indira; Prasad, Rajendra

doi:10.1016/j.ejmech.2010.07.050

Cited by 30 publications

(18 citation statements)

References 44 publications

(39 reference statements)

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“…Each half begins with a cytoplasmic hydrophilic nucleotide binding domain (NBD) followed by a highly hydrophobic transmembrane domain (TMD) (Figure 2). Each TMD comprises α-helices of six TMS (transmembrane segments), which creates the substrate promiscuity in the protein (Krishnamurthy et al, 1998a; Puri et al, 2010; Prasad et al, 2011). The NBDs bind and hydrolyse the ATP to drive drug efflux.…”

Section: Abc Proteins In Candidamentioning

confidence: 99%

“…A recent study provided an insight into the physico-chemical basis of substrate specificity of Cdr1p. For this, several compounds of diverse character were randomly selected and screened for their increased toxicity to S. cerevisiae strains over-expressing Cdr1p (Puri et al, 2010). On the basis of SAR of substrates and non-substrates, it was observed that, the substrates of Cdr1p had higher hydrophobicity index.…”

Section: Abc Proteins In Candidamentioning

confidence: 99%

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Efflux pump proteins in antifungal resistance

2014

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It is now well-known that the enhanced expression of ATP binding cassette (ABC) and major facilitator superfamily (MFS) proteins contribute to the development of tolerance to antifungals in yeasts. For example, the azole resistant clinical isolates of the opportunistic human fungal pathogen Candida albicans show an overexpression of Cdr1p and/or CaMdr1p belonging to ABC and MFS superfamilies, respectively. Hence, azole resistant isolates display reduced accumulation of therapeutic drug due to its rapid extrusion and that facilitates its survival. Considering the importance of major antifungal transporters, the focus of recent research has been to understand the structure and function of these proteins to design inhibitors/modulators to block the pump protein activity so that the drug already in use could again sensitize resistant yeast cells. The review focuses on the structure and function of ABC and MFS transporters of Candida to highlight the recent advancement in the field.

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Section: Abc Proteins In Candidamentioning

confidence: 99%

Section: Abc Proteins In Candidamentioning

confidence: 99%

Efflux pump proteins in antifungal resistance

2014

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“…It has been proposed that Cdr1p substrates generally possess a high hydrophobicity index. In addition, molecular branching, high aromaticity, and the presence of an atom-centered fragment (R-CH-R) are some of the other features that are essential for the substrates of Cdr1p (25). Notably, Cdr1p has a large number of aromatic residues in the binding pocket and has significant clustering of aromatic residues near the ectodomains.…”

Section: Cdr1p Is a Promiscuous Transportermentioning

confidence: 99%

The ABCs of Candida albicans Multidrug Transporter Cdr1

et al. 2015

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bIn the light of multidrug resistance (MDR) among pathogenic microbes and cancer cells, membrane transporters have gained profound clinical significance. Chemotherapeutic failure, by far, has been attributed mainly to the robust and diverse array of these proteins, which are omnipresent in every stratum of the living world. Candida albicans, one of the major fungal pathogens affecting immunocompromised patients, also develops MDR during the course of chemotherapy. The pivotal membrane transporters that C. albicans has exploited as one of the strategies to develop MDR belongs to either the ATP binding cassette (ABC) or the major facilitator superfamily (MFS) class of proteins. The ABC transporter Candida drug resistance 1 protein (Cdr1p) is a major player among these transporters that enables the pathogen to outplay the battery of antifungals encountered by it. The promiscuous Cdr1 protein fulfills the quintessential need of a model to study molecular mechanisms of multidrug transporter regulation and structure-function analyses of asymmetric ABC transporters. In this review, we cover the highlights of two decades of research on Cdr1p that has provided a platform to study its structure-function relationships and regulatory circuitry for a better understanding of MDR not only in yeast but also in other organisms.

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“…ABC transporter Cdr1p transports a huge array of structurally unrelated compounds and this promiscuity toward substrates is a characteristic feature of all the multidrug transporters and hence makes their functionality all the more complex to understand Puri et al 2010;Prasad and Rawal 2014). Cdr1p is an integral plasma membrane protein, with a predicted molecular weight of 170 kDa (Prasad and Goffeau 2012).…”

Section: Cdr1p a Major Abc Multidrug Transporter Of C Albicansmentioning

confidence: 99%

Candida Efflux ATPases and Antiporters in Clinical Drug Resistance

Prasad

Rawal

Shah

2016

Advances in Experimental Medicine and Biology

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An enhanced expression of genes encoding ATP binding cassette (ABC) and major facilitator superfamily (MFS) transport proteins are known to contribute to the development of tolerance to antifungals in pathogenic yeasts. For example, the azole resistant (AR) clinical isolates of the opportunistic human fungal pathogen Candida albicans show an overexpression of CDR1 and/or CaMDR1 belonging to ABC and MFS, superfamilies, respectively. The reduced accumulation (due to rapid efflux) of drugs in AR isolates confirms the role of efflux pump proteins in the development of drug tolerance. Considering the importance of major multidrug transporters, the focus of recent research has been to understand the structure and function of these proteins which could help to design inhibitors/modulators of these pump proteins. This chapter focuses on some aspects of the structure and function of yeast transporter proteins particularly in relation to MDR in Candida.

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Analysis of physico-chemical properties of substrates of ABC and MFS multidrug transporters of pathogenic Candida albicans

Cited by 30 publications

References 44 publications

Efflux pump proteins in antifungal resistance

Efflux pump proteins in antifungal resistance

The ABCs of Candida albicans Multidrug Transporter Cdr1

Candida Efflux ATPases and Antiporters in Clinical Drug Resistance

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