New antifungal 4-chloro-3-nitrophenyldifluoroiodomethyl sulfone reduces the Candida albicans pathogenicity in the Galleria mellonella model organism

Monika Staniszewska,Michalina Kazek,Roberto De Jesús González-Hernández,Małgorzata Gizińska,Héctor M Mora-Montes,Zbigniew Ochal

doi:10.1007/s42770-019-00140-z

Abstract

Candida albicans represents an interesting microorganism to study complex host-pathogen interactions and for the development of effective antifungals. Our goal was to assess the efficacy of 4-chloro-3-nitrophenyldifluoroiodomethyl sulfone (named Sulfone) against the C. albicans infections in the Galleria mellonella host model. We assessed invasiveness of CAI4 parental strain and mutants: kex2Δ/KEX2 and kex2Δ/kex2Δ in G. mellonella treated with Sulfone. We determined that KEX2 expression was altered following Sulfone treatment in G. mellonella-C. albicans infection model. Infection with kex2Δ/kex2Δ induced decreased inflammation and minimal fault in fitness of larvae vs CAI4. Fifty percent of larvae died within 4–5 days (P value < 0.0001) when infected with CAI4 and kex2Δ/KEX2 at 109 CFU/mL; survival reached 100% in those injected with kex2Δ/kex2Δ. Larvae treated with Sulfone at 0.01 mg/kg 30 min before infection with all C. albicans tested survived infection at 90–100% vs C. albicans infected-PBS-treated larvae. Hypersensitive to Sulfone, kex2Δ/kex2Δ reduced virulence in survival. KEX2 was down-regulated when larvae were treated with Sulfone: 30 min before and 2 h post-SC5314-wild-type infection respectively. kex2Δ/kex2Δ was able to infect larvae, but failed to kill host when treated with Sulfone. Sulfone can be used to prevent or treat candidiasis. G. mellonella facilitates studding of host-pathogen interactions, i.e., testing host vs panel of C. albicans mutants when antifungal is dosed.

Highlights

Since incidences and frequency of the Candida albicans infections dominate over non-albicans species, there is still needResponsible Editor: Celia Maria de Almeida SoaresFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, PolandKONDRAT&Partners, Al
We examined if the KEX2 expression is altered following the Sulfone treatment in the G. mellonella-C. albicans infection model
Using the mini-ura-blaster technique, we disrupted KEX2 to study its relevance in the C. albicans virulence in vivo

Summary

Introduction

Since incidences and frequency of the Candida albicans infections dominate over non-albicans species, there is still needResponsible Editor: Celia Maria de Almeida SoaresFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, PolandKONDRAT&Partners, Al. The serine protease encoded by KEX2 is among the C. albicans’ virulence factors that mediate its success as a pathogen. It is a representative of subtilisin family of proteins, processes enzymes, and its critical role in virulence was demonstrated previously [4,5,6,7,8]. As this approach still needs further analyses, here we continue studies assessing the Galleria mellonella-C. albicans infection model and the efficiency of novel antimicrobial agent. The results obtained using these insects can serve as a starting point to study the C. albicans pathogenesis and generate hypotheses to be further tested in vertebrate models

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Results

Conclusion