AUTHOR=Gandra Rafael M. , McCarron Pauraic , Viganor Livia , Fernandes Mariana Farias , Kavanagh Kevin , McCann Malachy , Branquinha Marta H. , Santos André L. S. , Howe Orla , Devereux Michael 

TITLE=In vivo Activity of Copper(II), Manganese(II), and Silver(I) 1,10-Phenanthroline Chelates Against Candida haemulonii Using the Galleria mellonella Model

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.00470

DOI=10.3389/fmicb.2020.00470

ISSN=1664-302X

ABSTRACT=<p><italic>Candida haemulonii</italic> is an emerging opportunistic pathogen resistant to most antifungal drugs currently used in clinical arena. Metal complexes containing 1,10-phenanthroline (phen) chelating ligands have well-established anti-<italic>Candida</italic> activity against different medically relevant species. This study utilized larvae of <italic>Galleria mellonella</italic>, a widely used model of <italic>in vivo</italic> infection, to examine <italic>C. haemulonii</italic> infection characteristics in response to different copper(II), manganese(II), and silver(I) chelates containing phen, which had demonstrated potent anti-<italic>C. haemulonii</italic> activity in a previous study. The results showed that <italic>C. haemulonii</italic> virulence was influenced by inoculum size and incubation temperature, and the host <italic>G. mellonella</italic> immune response was triggered in an inoculum-dependent manner reflected by the number of circulating immune cells (hemocytes) and observance of larval melanization process. All test chelates were non-toxic to the host in concentrations up to 10 μg/larva. The complexes also affected the <italic>G. mellonella</italic> immune system, affecting the hemocyte number and the expression of genes encoding antifungal and immune-related peptides (e.g., <italic>inducible metalloproteinase inhibitor protein</italic>, <italic>transferrin</italic>, <italic>galiomycin</italic>, and <italic>gallerimycin</italic>). Except for [Ag<sub>2</sub>(3,6,9-tdda)(phen)<sub>4</sub>].EtOH (3,6,9-tddaH<sub>2</sub> = 3,6,9-trioxoundecanedioic acid), all chelates were capable of affecting the fungal burden of infected larvae and the virulence of <italic>C. haemulonii</italic> in a dose-dependent manner. This work shows that copper(II), manganese(II), and silver(I) chelates containing phen with anti-<italic>C. haemulonii</italic> activity are capable of (i) inhibiting fungal proliferation during <italic>in vivo</italic> infection, (ii) priming an immune response in the <italic>G. mellonella</italic> host and (iii) affecting <italic>C. haemulonii</italic> virulence.</p>