Efflux-Mediated Antifungal Drug Resistance

Cannon, Richard D.; Lamping, Erwin; Holmes, Ann R.; Niimi, Kyoko; Baret, Philippe; Keniya, M.V.; Tanabe, Koichi; Niimi, Masakazu; Goffeau, André; Monk, Brian C.

doi:10.1128/cmr.00051-08

Cited by 492 publications

(417 citation statements)

References 384 publications

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“…This could be explained by reduced activity of transporter-mediated efflux pump, especially by the downregulated expressions of CDR1 and CDR2 (Figure 4). Interestingly, KAE alone caused the upregulation of MDR1 expression, correlated with the fact that CDR1, CDR2, and MDR1 controlled possibly by two transcriptional pathways contributed differentially to antifungal resistance in C. albicans (Cannon et al 2009). The combination of KAE/FLC could promote the intracellular accumulation of rhodamine 6G, implying that KAE might assist FLC by suppressing the efflux pump.…”

Section: Discussionmentioning

confidence: 99%

The roles of CDR1, CDR2, and MDR1 in kaempferol-induced suppression with fluconazole-resistant Candida albicans

Shao

Zhang

Wang

et al. 2015

Pharmaceutical Biology

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Context: Fungal infections caused by fluconazole-resistant Candida albicans are an intractable clinical problem, calling for new efficient antifungal drugs. Kaempferol, an active flavonoid, has been considered a potential candidate against Candida species. Objective: This work investigates the resistance reversion of kaempferol in fluconazole-resistant C. albicans and the underlying mechanism. Materials and methods: The antifungal activities of fluconazole and/or kaempferol were assessed by a series of standard procedures including broth microdilution method, checkerboard assay and time-kill (T-K) test in nine clinical strains as well as a standard reference isolate of C. albicans. Subsequently, the morphological changes, the efflux of rhodamine 6G, and the expressions of CDR 1, CDR 2, and MDR 1 were analysed by scanning electron microscope (SEM), inverted fluorescence microscope and quantitative reverse transcription polymerase chain reaction (qRT-PCR) in C. albicans z2003.Results: For all the tested C. albicans strains, the minimum inhibitory concentrations (MICs) of fluconazole and kaempferol ranged 0.25-32 and 128-256 mg/mL with a range of fractional inhibitory concentration index of 0.257-0.531. In C. albicans z2003, the expression of both CDR 1 and CDR 2 were decreased after exposure to kaempferol alone with negligible rhodamine 6G accumulation, while the expression of CDR 1, CDR 2 and MDR 1 were all decreased when fluconazole and kaempferol were used concomitantly with notable fluorescence of rhodamine 6G observed. Discussion and conclusion: Kaempferol-induced reversion in fluconazole-resistant C. albicans might be likely due to the suppression of the expression of CDR1, CDR2 and MDR1.ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

The roles of CDR1, CDR2, and MDR1 in kaempferol-induced suppression with fluconazole-resistant Candida albicans

Shao

Zhang

Wang

et al. 2015

Pharmaceutical Biology

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“…Nevertheless, we found a significant number of isolates for which no mutation in the CYP51A gene could be identified (2 out of 10, 20 %). Therefore, other unrelated mechanisms such as increased production of drug target CYP51A protein (Albarrag et al, 2011;Arendrup, et al, 2010;Camps et al, 2012) or overexpression of efflux pumps (Bowyer et al, 2012;Cannon et al, 2009;Manavathu et al, 1999;Slaven et al, 2002) should be considered. In conclusion, although the number of patients affected by azole-resistant A. fumigatus isolates was limited, strict supervision of clinical azoleresistant A. fumigatus isolates and persistent environmental screening of azole resistance are vital to the development of approaches for the management of azole resistance in human pathogenic fungi.…”

Section: Discussionmentioning

confidence: 99%

High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue?

Nabili

Shokohi

Moazeni

et al. 2016

Journal of Medical Microbiology

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Triazole antifungal agents are the mainstay of aspergillosis treatment. As highlighted in numerous studies, the global increase in the prevalence of triazole resistance could hamper the management of aspergillosis. In the present three-year study, 513 samples (213 clinical and 300 environmental samples) from 10 provinces of Iran were processed and screened in terms of azole resistance (4 and 1 mg l À1 of itraconazole and voriconazole, respectively), using selective plates. Overall, 150 A. fumigatus isolates (71 clinical and 79 environmental isolates) were detected. The isolates were confirmed by partial sequencing of the b-tubulin gene. Afterwards, in vitro antifungal susceptibility tests against triazole agents were performed, based on the Clinical and Laboratory Standards Institute (CLSI) M38-A2 document. The CYP51A gene was sequenced in order to detect mutations. The MIC of itraconazole against 10 (6.6 %) strains, including clinical (n=3, 4.2 %) and environmental (n=7, 8.8 %) strains, was higher than the breakpoint and epidemiological cut-off value. Based on the findings, the prevalence of azole-resistant A. fumigatus in Iran has increased remarkablyfrom 3.3 % to 6.6 % in comparison with earlier epidemiological research. Among resistant isolates, TR 34 /L98H mutations in the CYP51A gene were the most prevalent (n=8, 80 %), whereas other point mutations (F46Y, G54W, Y121F, G138C, M172V, F219C, M220I, D255E, T289F, G432C and G448S mutations) were not detected. Although the number of patients affected by azole-resistant A. fumigatus isolates was limited, strict supervision of clinical azole-resistant A. fumigatus isolates and persistent environmental screening of azole resistance are vital to the development of approaches for the management of azole resistance in human pathogenic fungi.

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“…ABC transporters are a major etiology of azole resistance in C. glabrata isolates [44] and disruption of azole efflux could allow for more concentrated intracellular azoles. Micafungin, on the other hand, is not an efflux pump substrate [45], potentially offering another explanation for the lack of effect with biguanide-micafungin combinations.…”

Section: Discussionmentioning

confidence: 99%

Biguanides enhance antifungal activity against Candida glabrata

Feliu

Lord

et al. 2018

Virulence

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Candida spp. are the fourth leading cause of nosocomial blood stream infections in North America. Candida glabrata is the second most frequently isolated species, and rapid development of antifungal resistance has made treatment a challenge. In this study, we investigate the therapeutic potential of metformin, a biguanide with well-established action for diabetes, as an antifungal agent against C. glabrata. Both wild type and antifungal-resistant isolates of C. glabrata were subjected to biguanide and biguanide-antifungal combination treatment. Metformin, as well as other members of the biguanide family, were found to have antifungal activity against C. glabrata, with MIC50 of 9.34 ± 0.16 mg/mL, 2.09 ± 0.04 mg/mL and 1.87 ± 0.05 mg/mL for metformin, phenformin and buformin, respectively. We demonstrate that biguanides enhance the activity of several antifungal drugs, including voriconazole, fluconazole, and amphotericin, but not micafungin. The biguanide-antifungal combinations allowed for additional antifungal effects, with fraction inhibition concentration indexes ranging from 0.5 to 1. Furthermore, metformin was able to lower antifungal MIC50 in voriconazole and fluconazole-resistant clinical isolates of C. glabrata. We also observed growth reduction of C. glabrata with rapamycin and an FIC of 0.84 ± 0.09 when combined with metformin, suggesting biguanide action in C. glabrata may be related to inhibition of the mTOR complex. We conclude that the biguanide class has direct antifungal therapeutic potential and enhances the activity of select antifungals in the treatment of resistant C. glabrata isolates. These data support the further investigation of biguanides in the combination treatment of serious fungal infections.

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Efflux-Mediated Antifungal Drug Resistance

Cited by 492 publications

References 384 publications

The roles of CDR1, CDR2, and MDR1 in kaempferol-induced suppression with fluconazole-resistant Candida albicans

The roles of CDR1, CDR2, and MDR1 in kaempferol-induced suppression with fluconazole-resistant Candida albicans

High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue?

Biguanides enhance antifungal activity against Candida glabrata

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