Clotrimazole Drug Resistance in Candida glabrata Clinical Isolates Correlates with Increased Expression of the Drug: H+ Antiporters CgAqr1, CgTpo1_1, CgTpo3, and CgQdr2
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For years, antifungal drug resistance in Candida species has been associated to the expression of ATP-Binding Cassette (ABC) multidrug transporters. More recently, a few drug efflux pumps from the Drug:H(+) Antiporter (DHA) family have also been shown to play a role in this process, although to date only the Candida albicans Mdr1 transporter has been demonstrated to be relevant in the clinical acquisition of antifungal drug resistance. This work provides evidence to suggest the involvement of the C. glabrata DHA transporters CgAqr1, CgQdr2, CgTpo1_1, and CgTpo3 in the clinical acquisition of clotrimazole drug resistance. A screening for azole drug resistance in 138 C. glabrata clinical isolates, from patients attending two major Hospitals in Portugal, was performed. Based on this screening, 10 clotrimazole susceptible and 10 clotrimazole resistant isolates were selected for further analysis. The transcript levels of CgAQR1, CgQDR2, CgTPO1_1, and CgTPO3 were found to be significantly up-regulated in resistant isolates when compared to the susceptible ones, with a level of correlation that was found to be similar to that of CgCDR2, an ABC gene known to be involved in the clinical acquisition of resistance. As a proof-of-concept experiment, the CgTPO3 gene was deleted in an azole resistant C. glabrata isolate, exhibiting high levels of expression of this gene. The deletion of CgTPO3 in this isolate was found to lead to decreased resistance to clotrimazole and fluconazole, and increased accumulation of azole drugs, thus suggesting the involvement of this transporter in the manifestation of azole resistance.
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Another possible resistance mechanism in C. glabrata may involve the major facilitator superfamily transporter TPO3, as its depletion results in increased sensitivity to fluconazole and clotrimazole.
“Another possible resistance mechanism in C. glabrata may involve the major facilitator superfamily (MFS) transporter, TPO3, as its depletion results in increased sensitivity to fluconazole and clotrimazole [100].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [100]
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Cites
Sanglard, D., Kuchler, K., Ischer, F., Pagani, J. L., Monod, M., & Bille, J. (1995) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.39.11.2378 · Cited by 815 · see citing works
The SAT1 flipper, an optimized tool for gene disruption in Candida albicans
Reuß, O., Vik, Å., Kolter, R., & Morschhäuser, J. (2004) · Gene · doi:10.1016/j.gene.2004.06.021 · Cited by 744 · see citing works
White, T. C. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.7.1482 · Cited by 612 · see citing works
Epidemiology and risk factors for invasive candidiasis
Yapar, N. (2014) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s40160 · Cited by 610 · see citing works
Efflux-Mediated Antifungal Drug Resistance
Cannon, R. D., Lamping, E., Holmes, A. R., Niimi, K., Baret, P. V., Keniya, M. V., Tanabe, K., Niimi, M., Goffeau, A., & Monk, B. C. (2009) · Clinical Microbiology Reviews · doi:10.1128/cmr.00051-08 · Cited by 608 · see citing works
Sanglard, D., Ischer, F., Calabrese, D., Majcherczyk, P. A., & Bille, J. (1999) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.43.11.2753 · Cited by 337 · see citing works
Sanguinetti, M., Posteraro, B., Fiori, B., Ranno, S., Torelli, R., & Fadda, G. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.2.668-679.2005 · Cited by 319 · see citing works
Emerging and Emerged Pathogenic Candida Species: Beyond the Candida albicans Paradigm
Papon, N., Courdavault, V., Clastre, M., & Bennett, R. J. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003550 · Cited by 314 · see citing works
Regulation of multidrug resistance in pathogenic fungi
Morschhäuser, J. (2010) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2009.08.002 · Cited by 300 · see citing works
Vermitsky, J.-P., & Edlind, T. D. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.10.3773-3781.2004 · Cited by 285 · see citing works
Candida glabrata: A review of its features and resistance
Rodrigues, C. F., Silva, S., & Henriques, M. (2014) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-013-2009-3 · Cited by 268 · see citing works
Treatment of epidemic and pandemic influenza with neuraminidase and M2 proton channel inhibitors
OXFORD, J. S., Bossuyt, S., Balasingam, S., Mann, A., Novelli, P., & Lambkin‐Williams, R. (2003) · Clinical Microbiology and Infection · doi:10.1046/j.1469-0691.2003.00564.x · Cited by 231 · see citing works
Mechanism of Increased Fluconazole Resistance in <i>Candida glabrata</i> during Prophylaxis
Bennett, J. E., Izumikawa, K., & Marr, K. A. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.5.1773-1777.2004 · Cited by 217 · see citing works
Henry, K. W., Nickels, J. T., & Edlind, T. D. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.10.2693-2700.2000 · Cited by 216 · see citing works
Rodríguez-Tudela, J. L., Barchiesi, F., Billé, J., Chryssanthou, E., Cuenca‐Estrella, M., Denning, D. W., Donnelly, J. P., Dupont, B., Fegeler, W., Moore, C. B., et al. (2003) · Clinical Microbiology and Infection · doi:10.1046/j.1469-0691.2003.00789.x · Cited by 208 · see citing works
Clotrimazole as a pharmaceutical: past, present and future.
Crowley, P. D., & Gallagher, H. C. (2014) · Journal of Applied Microbiology · doi:10.1111/jam.12554 · Cited by 203 · see citing works
Design, synthesis, and antifungal activity of triazole and benzotriazole derivatives
Rezaei, Z., Khabnadideh, S., Pakshir, K., Hossaini, Z., Amiri, F., & Assadpour, E. (2008) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2008.07.012 · Cited by 179 · see citing works
Martel, C. M., Parker, J. E., Bader, O., Weig, M., Gross, U., Warrilow, A. G. S., Rolley, N., Kelly, D. E., & Kelly, S. L. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00348-10 · Cited by 168 · see citing works
Miyazaki, H., Miyazaki, Y., Geber, A., Parkinson, T., Hitchcock, C. A., Falconer, D. J., Ward, D. J., Marsden, K. E., & Bennett, J. E. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.7.1695 · Cited by 162 · see citing works
Wirsching, S., Michel, S., & Morschhäuser, J. (2000) · Molecular Microbiology · doi:10.1046/j.1365-2958.2000.01899.x · Cited by 158 · see citing works
Roetzer, A., Gabaldón, T., & Schüller, C. (2011) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2010.02102.x · Cited by 154 · see citing works
Cuenca‐Estrella, M., Lee‐Yang, W., Ciblak, M. A., Arthington, B. A., Mellado, E., Warnock, D. W., & Rodrı́guez-Tudela, J. L. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.11.3644-3647.2002 · Cited by 134 · see citing works
MFS multidrug transporters in pathogenic fungi: do they have real clinical impact?
Costa, C., Dias, P. J., Sá‐Correia, I., & Teixeira, M. C. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00197 · Cited by 115 · see citing works
Self-citationA first Portuguese epidemiological survey of fungaemia in a university hospital
Costa‐de‐Oliveira, S., Pina‐Vaz, C., Mendonça, D. M., & Rodrigues, A. G. (2008) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-007-0448-4 · Cited by 97 · see citing works
Self-citationChen, K.-H., Miyazaki, T., Tsai, H., & Bennett, J. E. (2006) · Gene · doi:10.1016/j.gene.2006.08.010 · Cited by 95 · see citing works
Genomewide Expression Profile Analysis of the Candida glabrata Pdr1 Regulon
Caudle, K. E., Barker, K. S., Wiederhold, N. P., Xu, L., Homayouni, R., & Rogers, P. D. (2010) · Eukaryotic Cell · doi:10.1128/ec.00073-10 · Cited by 92 · see citing works
Pelletier, R., Peter, J., Antin, C., Gonzalez, C. E., Wood, L. V., & Walsh, T. J. (2000) · Journal of Clinical Microbiology · doi:10.1128/jcm.38.4.1563-1568.2000 · Cited by 90 · see citing works
Wirsching, S., Michel, S., Köhler, G., & Morschhäuser, J. (2000) · Journal of Bacteriology · doi:10.1128/jb.182.2.400-404.2000 · Cited by 88 · see citing works
Transcriptional profiling of azole-resistant Candida parapsilosis strains
Silva, A. P., Miranda, I. M., Guida, A., Synnott, J., Rocha, R., Silva, R., Amorim, A., Pina-Vaz, C., Butler, G., & Rodrigues, A. G. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01127-10 · Cited by 86 · see citing works
Self-citationPfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., & Diekema, D. J. (2007) · Journal of Clinical Microbiology · doi:10.1128/jcm.01551-06 · Cited by 77 · see citing works
Pfaller, M. A., Espinel‐Ingroff, A., Boyken, L. B., Hollis, R. J., Kroeger, J. S., Messer, S. A., Tendolkar, S., & Diekema, D. J. (2011) · Journal of Clinical Microbiology · doi:10.1128/jcm.02441-10 · Cited by 73 · see citing works
Rosa, M. F., & Sá‐Correia, I. (1996) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.1996.tb08000.x · Cited by 72 · see citing works
Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., & Diekema, D. J. (2004) · Journal of Clinical Microbiology · doi:10.1128/jcm.42.7.3137-3141.2004 · Cited by 66 · see citing works
Costa, C., Pires, C. M. B. F., Cabrito, T. R., Renaudin, A., Ohno, M., Chibana, H., Sá‐Correia, I., & Teixeira, M. C. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00811-12 · Cited by 65 · see citing works
Self-citationRodrı́guez-Tudela, J. L., Donnelly, J. P., Pfaller, M. A., Chryssantou, E., Warn, P. A., Denning, D. W., Espinel‐Ingroff, A., Barchiesi, F., & Cuenca‐Estrella, M. (2006) · Journal of Clinical Microbiology · doi:10.1128/jcm.01969-06 · Cited by 57 · see citing works
Cross, E. W., Park, S., & Perlin, D. S. (2000) · Microbial Drug Resistance · doi:10.1089/107662900419474 · Cited by 56 · see citing works
Pfaller, M. A., Messer, S. A., Boyken, L. B., Tendolkar, S., Hollis, R. J., & Diekema, D. J. (2007) · Journal of Clinical Microbiology · doi:10.1128/jcm.01952-07 · Cited by 55 · see citing works
Faria‐Ramos, I., Neves-Maia, J., Ricardo, E., Santos‐Antunes, J., Silva, A. P., Costa‐de‐Oliveira, S., Cantón, R., Rodrigues, A. G., & Pina‐Vaz, C. (2014) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-014-2194-8 · Cited by 55 · see citing works
Self-citationPais, P., Costa, C., Pires, C. M. B. F., Shimizu, K., Chibana, H., & Teixeira, M. C. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m114.045344 · Cited by 46 · see citing works
Self-citationCosta, C., Henriques, A., Pires, C., Nunes, J., Ohno, M., Chibana, H., Sá-Correia, I., & Teixeira, M. C. (2013) · Frontiers in Microbiology · doi:10.3389/fmicb.2013.00170 · Cited by 45 · see citing works
Self-citationMechanisms of azole resistance among clinical isolates of Candida glabrata in Poland
Szweda, P., Gucwa, K., Romanowska, E., Dzierżanowska‐Fangrat, K., Naumiuk, Ł., Brillowska‐Dąbrowska, A., Wojciechowska‐Koszko, I., & Milewski, S. (2015) · Journal of Medical Microbiology · doi:10.1099/jmm.0.000062 · Cited by 42 · see citing works
Costa, C., Nunes, J., Henriques, A., Mira, N. P., Nakayama, H., Chibana, H., & Teixeira, M. C. (2014) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dku044 · Cited by 41 · see citing works
Self-citationFaria‐Ramos, I., Neves-Maia, J., Ricardo, E., Santos‐Antunes, J., Silva, A. T., Costa‐de‐Oliveira, S., Cantón, R., Rodrigues, A. G., & Pina‐Vaz, C. (2015) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-015-2471-1 · Cited by 40 · see citing works
Self-citationCosta‐de‐Oliveira, S., Miranda, I. M., Silva, R. M., Silva, A. P., Rocha, R., Amorim, A., Rodrigues, A. G., & Pina‐Vaz, C. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00589-10 · Cited by 37 · see citing works
Self-citationPina‐Vaz, C., Sansonetty, F., Rodrigues, A. G., Costa‐de‐Oliveira, S., Martinez‐de‐Oliveira, J., & Fonseca, A. F. (2001) · Journal of Medical Microbiology · doi:10.1099/0022-1317-50-4-375 · Cited by 36 · see citing works
Self-citationAbbes, S., Mary, C., Sellami, H., Michel-Nguyen, A., Ayadi, A., & Ranque, S. (2013) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2013.00074 · Cited by 26 · see citing works
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- Authors
- Costa, C., Ribeiro, J., Miranda, I. M., Silva-Dias, A., Cavalheiro, M., Costa-de-Oliveira, S., Rodrigues, A. G., & Teixeira, M. C.
- Affiliations
- University of Lisbon (PT)
- Universidade do Porto (PT)
- Corresponding author
- Teixeira, Miguel C.
- ORCID
- Venue
- Frontiers in Microbiology
- Publisher
- Frontiers Media SA
- Published
- 2016-04-19
- Volume
- 7
- Pages
- 526-526
- ISSN
- 1664-302X (ISSN-L)
- PMC
- PMC4835504
- OpenAlex
- W2338841684
- Cited by
- 43
- References
- 46
- Citations by year
- 2026: 4 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 2
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Microbiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fundação para a Ciência e a Tecnologia (“PTDC/EBB-BIO/119356/2010, PTDC/BBB-BIO/4004/2014, UID/BIO/04565/2013, SFRH/BPD/100863/2014”)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Candida glabrata, clotrimazole resistance, azole resistance, gene expression, gene deletion, fluconazole, clinical isolates
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