Additive potential of combination therapy against cryptococcosis employing a novel amphotericin B and fluconazole loaded dual delivery system

Khan, Azmat Ali; Alanazi, Amer M.; Jabeen, Mumtaz; Khan, Shahanavaj; Malik, Abdul

doi:10.1016/j.ejps.2018.04.015

Cited by 10 publications

(7 citation statements)

References 42 publications

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“…FLC is the drug of choice for moderate pulmonary infections. For central nervous system infections, a combination of more expensive fungicidal drugs amphotericin B and flucytosine are administered [9, 10]; however, the combination of these two drugs produces more toxic side effects for the host.…”

Section: Introductionmentioning

confidence: 99%

Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans

et al. 2019

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Background: Cryptococcus neoformans, a basidiomycetous yeast, is a fungal pathogen that can colonize the lungs of humans causing pneumonia and fungal meningitis in severely immunocompromised individuals. Recent studies have implied that the antifungal drug fluconazole (FLC) can induce oxidative stress in C. neoformans by increasing the production of reactive oxygen species (ROS), as presence of the antioxidant ascorbic acid (AA) could reverse the inhibitory effects of FLC on C. neoformans. However, in Candida albicans, AA has been shown to stimulate the expression of genes essential for ergosterol biosynthesis. Hence, the contribution of ROS in FLC-mediated growth inhibition remains unclear. Results: In order to determine whether counteracting ROS generated by FLC in C. neoformans can contribute to diminishing inhibitory effects of FLC, we tested three other antioxidants in addition to AA, namely, pyrrolidine dithiocarbamate (PDTC), retinoic acid (RA), and glutathione (GSH). Our data confirm that there is an increase in ROS in the presence of FLC in C. neoformans. Importantly, all four antioxidants reversed FLC-mediated growth inhibition of C. neoformans to various extents. We further verified the involvement of increased ROS in FLC-mediated growth inhibition by determining that ROS-scavenging proteins, metallothioneins (CMT1 and CMT2), contribute to growth recovery by PDTC and AA during treatment with FLC. Conclusion: Our study suggests that ROS contributes to FLC-mediated growth inhibition and points to a complex nature of antioxidant-mediated growth rescue in the presence of FLC.

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Section: Introductionmentioning

confidence: 99%

Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans

et al. 2019

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“…If chitinase can be used in combination with AMB to exert higher antifungal activity, the dose of AMB may be able to be decreased, resulting in a decrease in the side effects caused by AMB, and this combination may be a useful method for treating fungal infections. Other researchers also investigated the combination of AMB with some antimycotic agents. , For instance, the combination of 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol (C1) with AMB to combat several pathogenic fungi has been reported in improving antifungal activity. The minimum inhibitory concentration (MIC) value of all pathogenic fungi differs depending on the concentration of C1.…”

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confidence: 99%

Enhancement of the Antifungal Activity of Chitinase by Palmitoylation and the Synergy of Palmitoylated Chitinase with Amphotericin B

et al. 2022

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Combinations of antifungal drugs can have synergistic antifungal activity, achieving high therapeutic efficacy while minimizing the side effects. Amphotericin B (AMB) has been used as a standard antifungal drug for fungal infections; however, because of its high toxicity, new strategies to minimize the required dose are desirable. Chitinases have recently received attention as alternative safe antifungal agents. Herein, we report the combination of palmitoylated chitinase domains with AMB to enhance the antifungal activity. The chitin-binding domain (LysM) from Pteris ryukyuensis chitinase was site-specifically palmitoylated by conjugation reaction catalyzed by microbial transglutaminase. The palmitoylated LysM (LysM-Pal) exhibited strong antifungal activity against Trichoderma viride, inhibiting the growth completely at a concentration of 2 μM. This antifungal effect of LysM-Pal was mainly due to the effect of anchoring of palmitic acid motif to the plasma membrane of fungi. A combination of AMB with LysM-Pal resulted in synergistic enhancement of the antifungal activity. Intriguingly, LysM-Pal exhibited higher level of antifungal activity enhancement than palmitoylated catalytic domain (CatD) and fusion of LysM and CatD. Addition of 0.5 μM LysM-Pal to AMB reduced the minimal inhibition concentration of AMB to 0.31 μM (2.5 μM without LysM-Pal). The possible mechanism of the synergistic effect of AMB and LysM-Pal is destabilization of the plasma membrane by anchoring of palmitic acid and ergosterol extraction by AMB and destabilization of the chitin layer by LysM binding. The combination of LysM-Pal with AMB can drastically reduce the dose of AMB and may be a useful strategy to treat fungal infections.

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“…Few studies have evaluated the efficacy of antifungal-impregnated PLGA carriers [22,23,24], although the release profile of amphotericin B with an organic solvent was shown to be promising. In the present study, PLGA/amphotericin B beads showed poor release dynamics [25].…”

Section: Discussionmentioning

confidence: 99%

Resorbable Beads Provide Extended Release of Antifungal Medication: In Vitro and In Vivo Analyses

Hsu

Chen

et al. 2019

Pharmaceutics

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Fungal osteomyelitis has been difficult to treat, with first-line treatments consisting of implant excision, radical debridement, and local release of high-dose antifungal agents. Locally impregnated antifungal beads are another popular treatment option. This study aimed to develop biodegradable antifungal-agent-loaded Poly(d,l-lactide-co-glycolide) (PLGA) beads and evaluate the in vitro/in vivo release patterns of amphotericin B and fluconazole from the beads. Beads of different sizes were formed using a compression-molding method, and their morphology was evaluated via scanning electron microscopy. Intrabead incorporation of antifungal agents was evaluated via Fourier-transform infrared spectroscopy, and in vitro fluconazole liberation curves of PLGA beads were inspected via high-performance liquid chromatography. When we implanted the drug-incorporated beads into the bone cavity of rabbits, we found that a high level of fluconazole (beyond the minimum therapeutic concentration [MTC]) was released for more than 49 d in vivo. Our results indicate that compression-molded PLGA/fluconazole beads have potential applications in treating bone infections.

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Additive potential of combination therapy against cryptococcosis employing a novel amphotericin B and fluconazole loaded dual delivery system

Cited by 10 publications

References 42 publications

Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans

Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans

Enhancement of the Antifungal Activity of Chitinase by Palmitoylation and the Synergy of Palmitoylated Chitinase with Amphotericin B

Resorbable Beads Provide Extended Release of Antifungal Medication: In Vitro and In Vivo Analyses

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