Candida Efflux ATPases and Antiporters in Clinical Drug Resistance

Abstract

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.

Selective BET bromodomain inhibition as an antifungal therapeutic strategy

“…This finding is consistent with the poor IC 50 values observed for JQ1 and PFI-1 towards Ca Bdf1 BDs. It also indicates that IBET-151 and bromosporine, which display (sub)micromolar IC 50 values, have poor cellular potency, possibly due to mechanisms known to reduce drug potency in C. albicans , including cell wall and plasma membrane permeability barriers3738 and the activity of efflux pumps leading to rapid drug extrusion3940. In summary, Ca Bdf1 and human BET BDs have distinct BETi-binding activity, supporting the feasibility of targeting Ca Bdf1 BDs with highly selective small-molecule inhibitors.…”

“…Most inhibitors, including compounds 1 and 2 , showed little antifungal activity against these strains. We speculate that the compounds failed to enter the fungal cell because of cellular permeability barriers3738, or were extruded by efflux pumps3940 or metabolized before a significant growth defect was detected. The most active compound was dibenzothiazepinone 3 , an analogue of 1 in which the cyclopropyl, oxadiazole and pyrazine groups are replaced by smaller methyl, carboxyamidyl and tetrahydrofuran groups, respectively (Fig.…”

LEGO‐Inspired Drug Design: Unveiling a Class of Benzo[d]thiazoles Containing a 3,4‐Dihydroxyphenyl Moiety as Plasma Membrane H+‐ATPase Inhibitors

“…ChemMedChem 2018, 13,37-47 www.chemmedchem.org etrate the cell membrane more easily than 40.F urthermore, compound 40 might be excluded from the cell by an efflux transporter;t his is aw ell-known drug tolerance mechanism. [21] An encouragingo bservation for these agentsi st he poor toxicity toward mammalian cells, as illustrated by the absence of cytotoxicity at concentrations below 90 mm (see Supporting Information).T he presents tudy encourages future investigation with the goal of improving membrane permeability of these derivatives, therebyg enerating Pma1p inhibitors for development as antifungal agents.…”

“…The precipitate was filtered and washed (3 10 mL) with CH 3 CN, EtOH, hot acetone, followed by recrystallization in EtOH to afford clean 1-15 as hydrochloride salts. General synthetic procedure for compounds [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30].Am ixture of 1-(substituted phenyl)ethan-1-one (1 equiv), copper(II) bromide (1 equiv), and 8mLo famixture of ethyl acetate/dichloromethane (1:1) was added to a2 0mLm icrowave reaction vial (Biotage). The vial was sealed and irradiated in am icrowave apparatus at 60 8C, high absorption for 15 min.…”

“…The crude product above was dissolved in 20 mL of CH 3 CN and the appropriately substituted heterocyclic thiol (1 equiv) was added and stirred at room temperature for 30 min until the appearance of as olid precipitate. The precipitate was then filtered and fast washed (3 10 mL) with each of CH 3 CN, EtOH, and hot acetone, followed by recrystallization in EtOH to afford clean [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] [1,4]dioxin-6-yl)-2-(quinolin-2-ylthio)ethan-1-one (16) Synthesis of 32-46:C ompounds 32-46 were synthesized using the same procedure as described for 1-15 from 31 a-o using microwave methodology (exception to workup procedure:a cidified to pH 4b yc onc. HBr instead of HCl, and products were collected as hydrobromide salts).…”