K21 Compound, a Potent Antifungal Agent: Implications for the Treatment of Fluconazole-Resistant HIV-Associated Candida Species.

Cathy N John,Dharam V Ablashi,Pedro M D S Abrantes,Charlene W J Africa,Bhupesh K Prusty

doi:10.3389/fmicb.2019.01021

Abstract

Background/Objectives: With mucocutaneous candidiasis being highly prevalent in HIV patients, the emergence of fluconazole-resistant Candida species forms a major challenge in treating and eradicating these infections. The objective of this study was to establish the antifungal activity of K21, a membrane-rupturing antimicrobial compound derived from a silica quaternary ammonium compound (SiQAC) with tetraethoxysilane (TEOS).Methods: The study sample included 81 Candida species of which 9 were type strains and 72 were clinical isolates. Minimum inhibitory concentrations, synergy, fractional inhibitory concentration index (FICI), and time kill assays were determined by broth microdilution. Electron microscopy (EM) was used to determine the qualitative changes brought about after treatment with K21.Results: K21 inhibited the growth of all fluconazole-resistant and susceptible Candida strains with only 2 h of exposure required to effectively kill 99.9% of the inoculum, and a definite synergistic effect was observed with a combination of K21 and fluconazole. EM demonstrated the presence of two forms of extracellular vesicles indicative of biofilm formation and cell lysis.Conclusion: The study established the efficacy of K21 as an antifungal agent and with fluconazole-resistant candidiasis on the increase, the development of K21 can provide a promising alternative to combat acquired drug resistance.

Highlights

The oral cavity may show the first signs and symptoms of HIV infection (Hirata, 2015), with the progression of HIV infection leading to frequent and recurrent episodes of highly severe oropharyngeal candidiasis (OPC) and systemic fungemia (Junqueira et al, 2012), often caused by fluconazole-resistant non-albicans Candida species (Mulu et al, 2013).K21, A Potent Antifungal AgentCurrently, five main classes of antifungal agents exist, each with its own particular cellular target and mode of action (Liu et al, 2014)
The present study aimed to evaluate K21 as an effective antifungal agent against resistant Candida species by establishing the time required by the compound to inhibit the growth of Candida species and demonstrating synergy between K21 and FCZ
Candida type strains were obtained from the American Type Culture Collections (ATCC, Manassas, VA) and National Collection of Pathogenic Fungi (NCPF, Public Health Culture Collections, England) and included Candida albicans (ATCC 90028 and NCPF 3281), Candida krusei (ATCC 2159), C. glabrata (ATCC 26512), Candida dubliniensis (NCPF 3949a), C. tropicalis (ATCC 950), C. parapsilosis (ATCC 22019), Candida lusitaniae (ATCC 34449), and Candida kefyr (ATCC 4135)

Summary

Introduction

Five main classes of antifungal agents exist, each with its own particular cellular target and mode of action (Liu et al, 2014). The triazoles (Fluconazole, Itraconazole, Voriconazole, Posaconazole and Isavuconazole) and allylamines (Naftifine and Terbinafine) inhibit synthesis of ergosterols by C14-demethylase and squalene epoxidase activity, respectively. The echinocandins (Caspofungin, Micafungin and Anidulafungin) interfere with cell wall synthesis. Damage to the cell wall results in disrupted membranes and as a result of osmotic fragility, cytoplasmic contents are spilled, thereby suppressing further fungal growth. The fluropyrimidine, 5-fluorocytosine, inhibits nucleic acid synthesis, interfering with normal cell metabolism, protein synthesis, a complete destruction of the cell interior and collapse of the cell wall (Kim et al, 2011)

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