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. 2020 Jan 16;10(1):498.
doi: 10.1038/s41598-019-57174-4.

Proton pump inhibitors act synergistically with fluconazole against resistant Candida albicans

Mengjiao Lu  1   2 , Haiying Yan  3 , Cuixiang Yu  4 , Lei Yuan  2 , Shujuan Sun  5
Affiliations

Proton pump inhibitors act synergistically with fluconazole against resistant Candida albicans

Mengjiao Lu et al. Sci Rep. .

Abstract

The incidence of resistant Candida isolates, especially Candida albicans, has increased continuously. To overcome the resistance, research on antifungal agent sensitizers has attracted considerable attention. Omeprazole and lansoprazole were found to inhibit the growth of sensitive C. albicans and hyphae formation in a high dose, respectively. This study aimed to determine the interactions of common clinically proton pump inhibitors (PPIs) and fluconazole both in vitro and in vivo and to further explore the possible mechanisms. In vitro, the tested PPIs all acted synergistically with fluconazole against both resistant C. albicans planktonic cells and biofilms preformed for ≤12 h with the minimum inhibitory concentration of fluconazole decreased from >512 μg/mL to 1-4 μg/mL. In vivo, PPIs plus fluconazole prolonged the survival rate of infected Galleria mellonella larvae by two-fold compared with that for the fluconazole monotherapy group and significantly reduced the tissue damage of infected larvae. Mechanism studies showed that PPIs significantly suppressed efflux pump activity, which is the common resistance mechanism of C. albicans, and significantly inhibited the virulence factors: phospholipase activity and morphology switching. These findings will provide new insights into antifungal agent discovery and potential approaches for the treatment of candidiasis caused by resistant C. albicans.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Three-dimensional model of PPIs combined with FLC against CA10 in vitro. (A–F) show the three-dimensional model of OME, LAN, PTP, RAB, ESO and ILA combined with FLC, respectively. The ΔE values are depicted on the z-axis, and the peaks above the 0 plane indicate synergistic combinations, whereas the peaks below the 0 plane indicate antagonistic combinations.
Figure 2
Figure 2
Survival rate of infected G. mellonella larvae treated with different drugs. After infection with CA10 (5 × 108 CFU/mL), larvae were treated with PBS, FLC (160 μg/mL), OME (80 µg/mL), LAN (80 µg/mL), PTP (160 µg/mL), RAB (40 µg/mL), ESO (80 µg/mL), ILA (40 µg/mL) or PPIs plus FLC (160 μg/mL). The log-rank test was performed, and results were compared with the FLC-treated group; *P < 0.05, **P < 0.01.
Figure 3
Figure 3
Histopathology of infected G. mellonella larvae treated with different drugs. After infection with CA10 (5 × 108 CFU/mL), larvae were treated with PBS, FLC (160 μg/mL), OME (80 µg/mL), RAB (40 µg/mL), OME (80 µg/mL) plus FLC (160 μg/mL) or RAB (40 µg/mL) plus FLC (160 μg/mL). The larvae of the blank groups were not treated with yeast or any drugs. Tissue sections were observed at a 4.2 × 10 multiplier, with a scale of 20 µm.
Figure 4
Figure 4
Effects of PPIs combined with FLC on the morphologic transformation of resistant C. albicans. A yeast suspension (5 × 105 CFU/mL) was incubated in RPMI-1640 medium with PBS, FLC (8 µg/mL), OME (128 µg/mL), OME (128 µg/mL) plus FLC (8 µg/mL), RAB (64 µg/mL) or RAB (64 µg/mL) plus FLC (8 µg/mL). After an incubation of 5 h at 35 °C, cells were observed under an inverted microscope at a 40 × 10 multiplier, and the scale in the figure is 20 µm.
Figure 5
Figure 5
Inhibitory effects of PPIs on the efflux of R6G in resistant C. albicans. Fluorescent intensity was detected after the treatment with OME (128 μg/mL) and RAB (64 μg/mL) over 240 min. The statistical significance was determined by Student’s t-test and compared with the control group; ***P < 0.001.
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References

    1. Kullberg BJ, Arendrup MC. Invasive Candidiasis. N. Engl. J. Med. 2015;373:1445–1456. doi: 10.1056/NEJMra1315399. - DOI - PubMed
    1. Cleveland AA, et al. Declining incidence of candidemia and the shifting epidemiology of Candida resistance in two US metropolitan areas, 2008–2013: results from population-based surveillance. PLoS one. 2015;10:e0120452. doi: 10.1371/journal.pone.0120452. - DOI - PMC - PubMed
    1. Polesello V, Segat L, Crovella S, Zupin L. Candida Infections and Human Defensins. Protein Pept. Lett. 2017;24:747–756. doi: 10.2174/0929866524666170807125245. - DOI - PubMed
    1. Azie N, et al. The PATH (Prospective Antifungal Therapy) Alliance(R) registry and invasive fungal infections: update 2012. Diagn. Microbiol. Infect. Dis. 2012;73:293–300. doi: 10.1016/j.diagmicrobio.2012.06.012. - DOI - PubMed
    1. Espinel-Ingroff A, et al. Multilaboratory study of epidemiological cutoff values for detection of resistance in eight Candida species to fluconazole, posaconazole, and voriconazole. Antimicrob. Agents Chemother. 2014;58:2006–2012. doi: 10.1128/AAC.02615-13. - DOI - PMC - PubMed

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