Octyl Gallate as an Intervention Catalyst to Augment Antifungal Efficacy of Caspofungin

Jong Kim,Luisa Cheng,Kathleen Chan

doi:10.3390/j1010004

Jong Kim, Luisa Cheng + Show 1 more

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https://doi.org/10.3390/j1010004

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Abstract

Filamentous fungi such as Aspergillus spp. are opportunistic pathogens, which cause highly invasive infections, especially in immunocompromised individuals. Control of such fungal pathogens is increasingly problematic due to the small number of effective drugs available for treatment. Moreover, the increased incidence of fungal resistance to antifungal agents makes this problem a global human health issue. The cell wall integrity system of fungi is the target of antimycotic drugs echinocandins, such as caspofungin (CAS). However, echinocandins cannot completely inhibit the growth of filamentous fungal pathogens, which results in survival/escape of fungi during treatment. Chemosensitization was developed as an alternative intervention strategy, where co-application of CAS with the intervention catalyst octyl gallate (OG; chemosensitizer) greatly enhanced CAS efficacy, thus achieved ≥99.9% elimination of filamentous fungi in vitro. Based on hypersensitive responses of Aspergillus antioxidant mutants to OG, it is hypothesized that, besides destabilizing cell wall integrity, the redox-active characteristic of OG may further debilitate the fungal antioxidant system.

Highlights

Fungal infectious diseases, such as candidiasis, cryptococcosis or invasive aspergillosis caused by Candida, Cryptococcus or Aspergillus, respectively, are serious human health issues, since effective drugs, especially those for eliminating resistant pathogens, are often very limited ([1] and the references therein)
The cell wall integrity system of fungal pathogens could serve as an effective target of antimycotic drugs [2]
CAS inhibits the activity of β-1,3-D-glucan synthase in the fungal cell wall integrity system, disrupting the synthesis of the cell wall component β-1,3-D-glucan ([5] and the references therein)

Summary

Introduction

Fungal infectious diseases, such as candidiasis, cryptococcosis or invasive aspergillosis caused by Candida, Cryptococcus or Aspergillus, respectively, are serious human health issues, since effective drugs, especially those for eliminating resistant pathogens, are often very limited ([1] and the references therein). The cell wall integrity system of fungal pathogens could serve as an effective target of antimycotic drugs [2]. Genome and functional studies revealed that many genes in the cell wall integrity system of fungi are well conserved [3,4]. Caspofungin (CAS; Figure 1), like other echinocandins including micafungin and anidulafungin, is an antifungal lipopeptide drug. CAS is in clinical use due to its good solubility, antifungal spectrum and pharmacokinetic properties. CAS inhibits the activity of β-1,3-D-glucan synthase in the fungal cell wall integrity system, disrupting the synthesis of the cell wall component β-1,3-D-glucan ([5] and the references therein). Echinocandins further lyse actively-growing hyphal tips during filamentous fungal growth [5]

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