Alkaloids solenopsins from fire ants display in vitro and in vivo activity against the yeast Candida auris

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Abstract
The urgency surrounding Candida auris as a public health threat is highlighted by both the Center for Disease Control (CDC) and World Health Organization (WHO) that categorized this species as a priority fungal pathogen. Given the current limitations of antifungal therapy for C. auris, particularly due to its multiple resistance to the current antifungals, the identification of new drugs is of paramount importance. Some alkaloids abundant in the venom of the red invasive fire ant (Solenopsis invicta), known as solenopsins, have garnered attention as potent inhibitors of bacterial biofilms, and there are no studies demonstrating such effects against fungal pathogens. Thus, we herein investigated the antibiotic efficacy of solenopsin alkaloids against C. auris biofilms and planktonic cells. Both natural and synthetic solenopsins inhibited the growth of C. auris strains from different clades, including fluconazole and amphotericin B-resistant isolates. Such alkaloids also inhibited matrix deposition and altered cellular metabolic activity of C. auris in biofilm conditions. Mechanistically, the alkaloids compromised membrane integrity as measured by propidium iodide uptake in exposed planktonic cells. Additionally, combining the alkaloids with AMB yielded an additive antifungal effect, even against AMB-resistant strains. Finally, both extracted solenopsins and the synthetic analogues demonstrated protective effect in vivo against C. auris infection in the invertebrate model Galleria mellonella. These findings underscore the potent antifungal activities of solenopsins against C. auris and suggest their inclusion in future drug development. Furthermore, exploring derivatives of solenopsins could reveal novel compounds with therapeutic promise.
Funding Information
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (311179/2017-7, 408711/2017-7)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES - 001)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance Code 001)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E-26/204.281/2021)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E-26/202.809/2018, E-26/201.032/2022)
  • National Institutes of Health (R21 AI124797)
  • National Natural Science Foundation of China (31772540)
  • Fapeg/CNPq (317847/2021-0)
  • Rede Micologia FAPERJ (E-26/211.300/2021)

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