Three structurally related oxathiolone fused chalcone derivatives appeared effective chemosensitizers, able to restore in part sensitivity to fluconazole of multidrug-resistant C. albicans strains. Compound 21 effectively chemosensitized cells resistant due to the overexpression of the MDR1 gene, compound 6 reduced resistance of cells overexpressing the ABC-type drug transporters CDR1/CDR2 and derivative 18 partially reversed fluconazole resistance mediated by both types of yeast drug efflux pumps. The observed effect of sensitization of resistant strains of Candida albicans to fluconazole activity in the presence of active compounds most likely resulted from inhibition of the pump-mediated efflux, as was revealed by the results of studies involving the fluorescent probes, Nile Red, Rhodamine 6G and diS-C3(3).

Department of Organic Chemistry Medical University of Gdańsk Gdańsk Poland

Department of Pharmaceutical Technology and Biochemistry Gdańsk University of Technology Gdańsk Poland

Faculty of Mathematics and Physics Charles University Prague Czech Republic

Membrane Biology Laboratory School of Life Sciences Jawaharlal Nehru University New Delhi India

Zobrazit více v PubMed

Balzi E., Chen W., Ulaszewski S., Capieaux E., Goffeau A. (1987). The multidrug resistance gene PDR1 from Saccharomyces cerevisiae. J. Biol. Chem. 262, 16871–16879. PubMed

Čadek R., Chládková K., Sigler K., Gášková D. (2004). Impact of the growth phase on the activity of multidrug resistance pumps and membrane potential of S. cerevisiae: effect of pump overproduction and carbon source. Biochim. Biophys. Acta 1665, 111–117. 10.1016/j.bbamem.2004.06.020 PubMed DOI

Clinical Laboratory Standards Institute (2008). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts-Second Edition. Approved Standard M27-A3. Wayne, PA: CLSI.

Conseil G., Baubichon-Cortay H., Dayan G., Jault J. M., Barron D., Di Pietro A. (1998). Flavonoids: a class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein. Proc. Natl. Acad. Sci. U.S.A. 95, 9831–9836. 10.1073/pnas.95.17.9831 PubMed DOI PMC

Conseil G., Decottignies A., Jault J. M., Comte G., Barron D., Goffeau A., et al. . (2000). Prenyl-flavonoids as potent inhibitors of the Pdr5p multidrug ABC transporter from Saccharomyces cerevisiae. Biochemistry 39, 6910–6917. 10.1021/bi000040f PubMed DOI

Decottignies A., Grant A. M., Nichols J. W., de Wet H., McIntosh D. B., Goffeau A. (1998). ATP-ase and multidrug transport activities of overexpressed yeast ABC protein Yor1p. J. Biol. Chem. 273, 12612–12622. 10.1074/jbc.273.20.12612 PubMed DOI

Dimmock J. R., Elias D. W., Beazely M. A., Kandepu N. M. (1999). Bioactivities of chalcones. Curr. Med. Chem. 6, 1125–1149. PubMed

Diwischek F., Morschhäuser J., Holzgrabe U. (2009). Cerulenin analogues as inhibitors of efflux pumps in drug-resistant Candida albicans. Arch. Pharm. (Weinheim) 342, 150–164. 10.1002/ardp.200800160 PubMed DOI

Franz R., Kelly S. L., Lamb D. C., Kelly D. E., Ruhnke M., Morschhäuser J. (1998). Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains. Antimicrob. Agents Chemother. 42, 3065–3072. PubMed PMC

Franz R., Ruhnke M., Morschhäuser J. (1999). Molecular aspects of fluconazole resistance development in Candida albicans. Mycoses 42, 453–458. 10.1046/j.1439-0507.1999.00498.x PubMed DOI

Gupta V., Kohli A., Krishnamurthy S., Puri N., Aalamgeer S. A., Panwar S., et al. . (1998). Identification of polymorphic mutant alleles of CaMDR1, a major facilitator of C. albicans which confers multidrug resistance and its in vitro transcriptional activation. Curr. Genet. 34, 192–199. 10.1007/s002940050385 PubMed DOI

Hendrych T., Kodedová M., Sigler K., Gášková D. (2009). Characterization of the kinetics and mechanisms of inhibition of drugs interacting with the S. cerevisiae multidrug resistance pumps Pdr5p and Snq2p. Biochim. Biophys. Acta 1788, 717–723. 10.1016/j.bbamem.2008.12.001 PubMed DOI

Holmes A. R., Keniya M. V., Ivnitski-Steele I., Monk B. C., Lamping E., Sklar L. A., et al. . (2012). The monoamine oxidase A inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates. Antimicrob. Agents Chemother. 56, 1508–1515. 10.1128/AAC.05706-11 PubMed DOI PMC

Ivanova A., Batovska D., Engi H., Parushev S., Ocsovszki I., Kostova I., et al. . (2008). MDR-reversal activity of chalcones. In Vivo 22, 379–384. PubMed

Ivnitski-Steele I., Holmes A. R., Lamping E., Monk B. C., Cannon R. D., Sklar L. A. (2009). Identification of Nile red as a fluorescent substrate of the Candida albicans ATP-binding cassette transporters Cdr1p and Cdr2p and the major facilitator superfamily transporter Mdr1p. Anal. Biochem. 394, 87–91. 10.1016/j.ab.2009.07.001 PubMed DOI PMC

Keniya M. V., Fleischer E., Klinger A., Cannon R. D., Monk B. C. (2015). Inhibitors of the Candida albicans Major Facilitator Superfamily transporter Mdr1p responsible for fluconazole resistance. PLoS ONE 10:e0126350. 10.1371/journal.pone.0126350 PubMed DOI PMC

Konieczny M. T., Konieczny W., Pirska D., Bułakowska A., Sabisz M., Składanowski A., et al. (2007a). Synthesis of oxathiolone fused chalcones bearing O-aminoalkyl side chain. Comparison of stability of isomeric benzoxathiolones under alkylation reaction conditions. Heterocycles 71, 2595–2615. 10.3987/COM-07-11165 DOI

Konieczny M. T., Konieczny W., Sabisz M., Składanowski A., Wakieć R., Augustynowicz-Kopeć E., et al. . (2007b). Acid-catalyzed synthesis of oxathiolone fused chalcones. Comparison of their activity toward various microorganisms and human cancer cells line. Eur. J. Med. Chem. 42, 729–733. 10.1016/j.ejmech.2006.12.014 PubMed DOI

Konieczny M. T., Konieczny W., Sabisz M., Składanowski A., Wakieć R., Augustynowicz-Kopeć E., et al. . (2007c). Synthesis of isomeric, oxathiolone fused chalcones and comparison of their activity toward various microorganisms and human cancer cells line. Chem. Pharm. Bull. 55, 817–820. 10.1248/cpb.55.817 PubMed DOI

Ła̧cka I., Konieczny M. T., Bułakowska A., Rzymowski T., Milewski S. (2011). Antifungal action of the oxathiolone fused chalcone derivative. Mycoses 54, e407–e414. 10.1111/j.1439-0507.2010.01936.x PubMed DOI

Liu X. L., Tee H. W., Go M. L. (2008). Functionalized chalcones as selective inhibitors of P-glycoprotein and breast cancer resistance protein. Bioorg. Med. Chem. 16, 171–180. 10.1016/j.bmc.2007.10.006 PubMed DOI

López S. N., Castelli M. V., Zacchino S. A., Domiìnguez J. N., Lobo G., Charris-Charris J., et al. . (2001). In vitro antifungal evaluation and structure–activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall. Bioorg. Med. Chem. 9, 1999–2013. 10.1016/S0968-0896(01)00116-X PubMed DOI

Marchetti O., Moreillon P., Glauser M. P., Bille J., Sanglard D. (2000). Potent synergism of the combination of fluconazole and cyclosporine in Candida albicans. Antimicrob. Agents Chemother. 44, 2373–2381. 10.1128/AAC.44.9.2373-2381.2000 PubMed DOI PMC

Milewski S., Mignini F., Borowski E. (1991). Synergistic action of nikkomycin X/Z with azole antifungals on Candida albicans. J. Gen. Microbiol. 137, 2155–2161 10.1099/00221287-137-9-2155 PubMed DOI

Nowakowska Z. (2007). A review of anti-infective and anti-inflammatory chalcones. Eur. J. Med. Chem. 42, 125–137. 10.1016/j.ejmech.2006.09.019 PubMed DOI

Odds F. C. (2003). Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 52, 1. 10.1093/jac/dkg301 PubMed DOI

Pfaller M. A., Diekema D. J. (2007). Epidemiology of invasive candidiasis: a persistent public health problem. Clin. Microbiol. Rev. 20, 133–163. 10.1128/CMR.00029-06 PubMed DOI PMC

Pfaller M. A. (2012). Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am. J. Med. 125, S3–S13. 10.1016/j.amjmed.2011.11.001 PubMed DOI

Prasad R., De Wergifosse P., Goffeau A. (1998). Molecular cloning and characterization of a novel gene of Candida albicans, CDR1 conferring multiple resistance to drugs and antifungals. Curr. Genet. 27, 320–329. 10.1007/BF00352101 PubMed DOI

Prasad R., Goffeau A. (2012). Yeast ATP-binding cassette transporters conferring multidrug resistance. Ann. Rev. Microbiol. 66, 37–61. 10.1146/annurev-micro-092611-150111 PubMed DOI

Prasad R., Panwar S. L., Smriti (2002). Drug resistance in yeasts – an emerging scenario. Adv. Microb. Physiol. 46, 155–201. 10.1016/S0065-2911(02)46004-3 PubMed DOI

Ricardo E., Costa-de-Oliveira S., Dias A. S., Guerra J., Rodrigues A. G., Pina-Vaz C. (2009). Ibuprofen reverts antifungal resistance on Candida albicans showing overexpression of CDR genes. FEMS Yeast Res. 9, 618–625. 10.1111/j.1567-1364.2009.00504.x PubMed DOI

Sanglard D., Odds F. C. (2002). Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect. Dis. 2, 73–85. 10.1016/S1473-3099(02)00181-0 PubMed DOI

Sharma A., Chakravarti B., Gupta M. P., Siddiqui J. A., Konwar R., Tripathi R. P. (2010). Synthesis and anti breast cancer activity of biphenyl based chalcones. Bioorg. Med. Chem. 18, 4711–4720. 10.1016/j.bmc.2010.05.015 PubMed DOI

Sharma M., Manoharlal R., Shukla S., Puri N., Prasad T., Ambudkar S. V., et al. . (2009). Curcumin modulated efflux mediated by yeast ABC multidrug transporters and is synergistic with antifungals. Antimicrob. Agents Chemother. 53, 3256–3265. 10.1128/AAC.01497-08 PubMed DOI PMC

Smriti Krishnamurthy, S., Dixit B. L., Gupta C. M., Milewski S., Prasad R. (2002). ABC transporters Cdr1p, Cdr2p and Cdr3p of a human pathogen Candida albicans are general phospholipid translocators. Yeast 19, 303–318. 10.1002/yea.818 PubMed DOI

Srinivasan A., Lopez-Ribot J. L., Ramasubramanian A. K. (2012). Overcoming antifungal resistance. Drug Discov. Today Technol. 11, 65–71. 10.1016/j.ddtec.2014.02.005 PubMed DOI PMC

Wink M., Ashour M. L., Zaki El-Readi M. (2012). Secondary metabolites from plants inhibiting ABC transporters and reversing resistance of cancer cells and microbes to cytotoxic and antimicrobial agents. Front. Microbiol. 3:130. 10.3389/fmicb.2012.00130 PubMed DOI PMC