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Styrylquinolines are heterocyclic compounds that are known for their antifungal and antimicrobial activity. Metal complexation through hydroxyl groups has been claimed to be a plausible mechanism of action for these types of compounds. A series of novel structures with protected hydroxyl groups have been designed and synthesized to verify the literature data. Their antifungal activity against wild-type Candida albicans strain and mutants with silenced efflux pumps activity has been determined. Combinations with fluconazole revealed synergistic interactions that were dependent on the substitution pattern. These results open a new route for designing active antifungal agents on a styrylquinoline scaffold.

Background The multicomponent primary active ATP-binding cassette transporter Cdr1p in the structure of the pathogenic yeast Candida albicans is among the culprits of antifungal agent resistance reported in recent decades. So far, various potential novel inhibitors/ modulators of this protein have been purified, synthesized, and biologically tested, with results showing their ability to effectively reverse CaCdr1p-mediated drug resistance phenomenon. These compounds are of diverse origins, possess non-identical structural features and adopt different mechanisms of action. Method A structured search of chemical features and mechanisms of studied modulators of CaCdr1p was carried out using both original research publications and review articles. The nature of possible inhibitory mechanisms against the pump was analyzed in relation to the structure and the activity of the transporter. A process of summarizing modulatory spectra of the listed compounds against 2 other efflux pumps of Candida albicans namely Cdr2p and Mdr1p was also conducted, during which selective inhibitors of Cdr1p were revealed. Results In this article, 6 possible mechanisms with which a molecule can manifest their activity against the efflux pump are described, and a list of nearly 50 CaCdr1p modulators found in literatures along with their respective mechanism(s) (if already identified) is provided, summarizing the results obtained so far in the search of new inhibitors of the drug extrusion transporter that can enhance the potency of commonly used antifungal agents. A table of inhibitory spectra of the listed compounds against Cdr1p, Cdr2p and Mdr1p is also given, with several selective modulators of Cdr1p finally indicated. Conclusion The findings of this review contribute to future studies regarding CaCdr1p and its modulators by summarizing the results obtained so far on this emerging issue of health sciences. Further research concerning novel compounds capable of inhibiting Cdr1p needs to be carried out in hopes of completing the lists provided in this article.

Styrylquinolines are a novel group of quinoline drugs that are known to have p53-independent antiproliferative activity and antiviral properties. This study evaluated the antifungal activity of these drugs more deeply, particularly their activity modulation towards Cdr1p, the main multidrug transporter of Candida albicans. Styrylquinolines were found to have antifungal activity and to work synergistically with fluconazole. Additionally, they decreased the extracellular concentration of rhodamine 6G in ABC-transporter-expressing cells. The cellular localization of GFP-tagged Cdr1p was assessed by epifluorescent microscopy. Styrylquinolines induce expression of Cdr1p, as confirmed by Western blotting. Three of four drugs tested caused the partial delocalization of transport protein to the cytoplasm. These results show the first evidence that styrylquinolines decrease the activity of ABC multidrug transporters in C. albicans.

In view of the importance of Candida Drug Resistance Protein (Cdr1p) of pathogenic Candida albicans in azole resistance, we have characterized its ability to efflux variety of substrates by subjecting its entire transmembrane segment (TMS) 5 to site directed mutagenesis. All the mutant variants of putative 21 amino acids of TMS 5 and native CaCdr1p were over expressed as a GFP-tagged protein in a heterologous host Saccharomyces cerevisiae. Based on the drug susceptibility pattern, the mutant variants could be grouped into two categories. The variants belonging to first category were susceptible to all the tested drugs, as compared to those belonging to second category which exhibited resistance to selective drugs. The mutant variants of both the categories were analyzed for their ATP catalysis and drug efflux properties. Irrespective of the categories, most of the mutant variants of TMS 5 showed an uncoupling between ATP hydrolysis and drug efflux. The mutant variants such as M667A, F673A, I675A and P678A were an exception since they reflected a sharp reduction in both Km and Vmax values of ATPase activity when compared with WT CaCdr1p-GFP. Based on the competition experiments, we could identify TMS 5 residues which are specific to interact with select drugs. TMS 5 residues of CaCdr1p thus not only impart substrate specificity but also selectively act as a communication link between ATP hydrolysis and drug transport.