A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen
Candida albicans
Authors: Fallah Sara , Duncan Dustin , Reichl Kyle D. , Smith Michael J. , Wang Wenyu , Porco John A. , Brown Lauren E. , Whitesell Luke , Robbins Nicole , Cowen Leah E. 
Published: February 2024

ABSTRACT

Candida albicans
, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandins. Alarmingly, the efficacy of these antifungals against
C. albicans
is hindered both by basal tolerance toward the drugs and the development of resistance mechanisms such as alterations of the drug’s target, modulation of stress responses, and overexpression of efflux pumps. Thus, the need to identify novel antifungal strategies is dire. To address this challenge, we screened 3,049 structurally-diverse compounds from the Boston University Center for Molecular Discovery (BU-CMD) chemical library against a
C. albicans
clinical isolate and identified 17 molecules that inhibited
C. albicans
growth by >80% relative to controls. Among the most potent compounds were CMLD013360, CMLD012661, and CMLD012693, molecules representing two distinct chemical scaffolds, including 3-hydroxyquinolinones and a xanthone natural product. Based on structural insights, CMLD013360, CMLD012661, and CMLD012693 were hypothesized to exert antifungal activity through metal chelation. Follow-up investigations revealed all three compounds exerted antifungal activity against non-albicans
Candida
, including
Candida auris
and
Candida glabrata
, with the xanthone natural product CMLD013360 also displaying activity against the pathogenic mould
Aspergillus fumigatus
. Media supplementation with metallonutrients, namely ferric or ferrous iron, rescued
C. albicans
growth, confirming these compounds act as metal chelators. Thus, this work identifies and characterizes two chemical scaffolds that chelate iron to inhibit the growth of the clinically relevant fungal pathogen
C. albicans

IMPORTANCE

The worldwide incidence of invasive fungal infections is increasing at an alarming rate. Systemic candidiasis caused by the opportunistic pathogen
Candida albicans
is the most common cause of life-threatening fungal infection. However, due to the limited number of antifungal drug classes available and the rise of antifungal resistance, an urgent need exists for the identification of novel treatments. By screening a compound collection from the Boston University Center for Molecular Discovery (BU-CMD), we identified three compounds representing two distinct chemical scaffolds that displayed activity against
C. albicans
. Follow-up analyses confirmed these molecules were also active against other pathogenic fungal species including
Candida auris
and
Aspergillus fumigatus
. Finally, we determined that these compounds inhibit the growth of
C. albicans
in culture through iron chelation. Overall, this observation describes two novel chemical scaffolds with antifungal activity against diverse fungal pathogens.