Streptomyces albidoflavus
Q antifungal metabolites inhibit the ergosterol biosynthesis pathway and yeast growth in fluconazole-resistant
Candida glabrata
: phylogenomic and metabolomic analyses
Authors: Bautista-Crescencio Celia , Casimiro-Ramos Arturo , Fragoso-Vázquez M. Jonathan , Correa-Basurto José , Olano Carlos , Hernández-Rodríguez César , Villa-Tanaca Lourdes 
Published: September 2023

ABSTRACT

There is an urgent need to develop new antifungals due to the increasing prevalence of multidrug-resistant fungal infections and the recent emergence of COVID-19-associated candidiasis. A good study model for evaluating new antifungal compounds is
Candida glabrata
, an opportunistic fungal pathogen with intrinsic resistance to azoles (the most common clinical drugs for treating fungal infections). The aim of the current contribution was to conduct
in vitro
tests of antifungal metabolites produced by the bacteria
Streptomyces albidoflavus
Q, identify their molecular structures, and utilize several techniques to provide evidence of their therapeutic target.
S. albidoflavus
was isolated from maize rhizospheric soil in Mexico and identified by phylogenomic analysis using a 92-gene core. Of the 66 metabolites identified in
S. albidoflavus
Q by a liquid chromatography-high resolution mass spectrometry (LC-HRMS) metabolomic analysis of the lyophilized supernatant, six were selected by the Way2drug server based on their
in silico
binding to the likely target, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR, the key enzyme in the ergosterol biosynthesis pathway). Molecular modeling studies show a relatively high binding affinity for the
Cg
HMGR enzyme by two secondary metabolites: isogingerenone B (diaryl heptanoid) and notoginsenoside J (polycyclic triterpene). These secondary metabolites were able to inhibit ergosterol synthesis and affect yeast viability
in vitro
. They also caused alterations in the ultrastructure of the yeast cytoplasmic membrane, as evidenced by transmission electron microscopy. The putative target of isogingerenone B and notoginsenoside J is distinct from that of azole drugs (the most common clinical antifungals). The target for the latter is the lanosterol 14 alpha-demethylase enzyme (Erg11).

IMPORTANCE

Multidrug resistance has emerged among yeasts of the genus
Candida
, posing a severe threat to global health. The problem has been exacerbated by the pandemic associated with COVID-19, during which resistant strains of
Candida auris
and
Candida glabrata
have been isolated from patients infected with the SARS-CoV-2 virus. To confront this challenge, the World Health Organization has invoked scientists to search for new antifungals with alternative molecular targets. This study identified 66 metabolites produced by the bacteria
Streptomyces albidoflavus
Q, 6 of which had promising properties for potential antifungal activity. The metabolites were tested
in vitro
as inhibitors of ergosterol synthesis and
C. glabrata
growth, with positive results. They were also found to damage the cytoplasmic membrane of the fungus. The corresponding molecular structures and their probable therapeutic target were established. The target is apparently distinct from that of azole drugs.