Antifungal Potential of Copper(II), Manganese(II) and Silver(I) 1,10-Phenanthroline Chelates Against Multidrug-Resistant Fungal Species Forming the Candida haemulonii Complex: Impact on the Planktonic and Biofilm Lifestyles.

Rafael M Gandra,André L S Santos,Pauraic Mc Carron,Mariana F Fernandes,Marta H Branquinha,Michael Devereux,Malachy Mccann,Ana Carolina Aor,Thaís P Mello,Lívia S Ramos

doi:10.3389/fmicb.2017.01257

Abstract

Candida haemulonii, Candida haemulonii var. vulnera and Candida duobushaemulonii, which form the C. haemulonii complex, are emerging etiologic agents of fungal infections known to be resistant to the most commonly used antifungals. The well-established anti-Candida potential of metal complexes containing 1,10-phenanthroline (phen) ligands encouraged us to evaluate different copper(II), manganese(II), and silver(I) phen chelates for their ability to inhibit planktonic growth and biofilm of C. haemulonii species complex. Two novel coordination complexes, {[Cu(3,6,9-tdda)(phen)2].3H2O.EtOH}n and [Ag2(3,6,9-tdda)(phen)4].EtOH (3,6,9-tddaH2 = 3,6,9-trioxaundecanedioic acid), were synthesized in a similar fashion to the other, previously documented, sixteen copper(II), manganese(II), and silver(I) chelates employed herein. Three isolates of each C. haemulonii species complex were used and the effect of the metal chelates on viability was determined utilizing the CLSI standard protocol and on biofilm-growing cells using the XTT assay. Cytotoxicity of the chelates was evaluated by the MTT assay, employing lung epithelial cells. The majority of the metal chelates were capable of interfering with the viability of planktonic-growing cells of all the fungal isolates. The silver complexes were the most effective drugs (overall geometric mean of the minimum inhibitory concentration (GM-MIC) ranged from 0.26 to 2.16 μM), followed by the manganese (overall GM-MIC ranged from 0.87 to 10.71 μM) and copper (overall GM-MIC ranged from 3.37 to >72 μM) chelates. The manganese chelates (CC50 values ranged from 234.51 to >512 μM) were the least toxic to the mammalian cells, followed by the silver (CC50 values ranged from 2.07 to 13.63 μM) and copper (CC50 values ranged from 0.53 to 3.86 μM) compounds. When tested against mature biofilms, the chelates were less active, with MICs ranging from 2- to 33-fold higher levels when compared to the planktonic MIC counterparts. Importantly, manganese(II), copper(II), and silver(I) phen chelates are relatively cheap and easy to synthesize and they offer significant antifungal chemotherapeutic potential for the treatment of highly resistant pathogens.

Highlights

The global incidences of invasive candidiasis has increased considerably in recent decades, being the fourth and sixth leading cause of nosocomial blood infections in the United States of America and Europe, respectively (Caggiano et al, 2015)
The chemical structures of chelates 1–18 are presented in Figure 1
With the exceptions of 1, 2, and 4, the copper(II) complexes demonstrated moderate to good antifungal activity

Summary

Introduction

The global incidences of invasive candidiasis has increased considerably in recent decades, being the fourth and sixth leading cause of nosocomial blood infections in the United States of America and Europe, respectively (Caggiano et al, 2015). Infections caused by non-albicans Candida species, such as Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei, are becoming increasingly more common in hospital settings (Abu-Elteen and Hamad, 2012; Ramos et al, 2015) This new scenario constitutes a clinical challenge, since such nonalbicans Candida species are more resistant to the different classes of antifungal drugs that are currently available (AbuElteen and Hamad, 2012; Ramos et al, 2015). Given the epidemiological profile of the C. haemulonii complex and the fact that it is resistant to such a broad spectrum of the state-of-the-art antifungals (e.g., amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, micafungin, and caspofungin) (Giusiano et al, 2005; Khan et al, 2007; Kim et al, 2009; Ruan et al, 2010), it is imperative that the scientific community examine alternative therapeutic paths for it treatment Aggravating this scenario, recently, our research group described the ability of C. haemulonii species complex to form biofilm on inert substrate (Ramos et al, 2017). Anti-biofilm strategies able to prevent and/or eradicate fungal biofilms in medical devices are urgently required (Ramage et al, 2014; Ramos et al, 2017)

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