Le Pape, P. | bioRxiv Science

bioRxiv2025

Varied mutual growth inhibition between commensal yeasts and strains

Interkingdom interactions between bacteria and fungi are an emerging research field that provides insights into pathological, environmental, and microbiota-related relationships. However, the mechanisms governing these interactions, particularly in the context of microbial resistance, remain largely unknown. This study aims to enhance our understanding of the complex interactions between different Candida, Nakaseomyces and Sacharomyces species from the human microbiota and two not isogenic strains of Escherichia coli (antibiotic-susceptible E. coli-ATCC and multidrug-resistant E. coli-OXA48). Forty-nine Candida strains were co-cultured with the two E. coli strains. Both bacterial and yeast growth was monitored using flow cytometry and compared to monocultures. The effect of yeast culture supernatants on E. coli proliferation was also investigated. Metabolomic fingerprints and metabolite identification were performed using mass spectrometry-based approaches followed by multiblock statistical analyses. The inhibitory powers (IP) of yeasts against E. coli and vice versa varied significantly among fungal species. N. glabrata exhibited the strongest inhibition against E. coli-ATCC, while Candida lusitaniae, C. kefyr, C. krusei, C. tropicalis, and C. dubliniensis showed lower IPs. C. parapsilosis and Saccharomyces cerevisiae had no inhibitory effects. Against E. coli-OXA48, most yeasts displayed no inhibition, except for N. glabrata. Conversely, E. coli inhibited yeast growth more effectively, particularly Candida albicans. Fungal supernatants from S. cerevisiae, C. lusitaniae, and N. glabrata showed the highest inhibitory effects on E. coli-ATCC, while S. cerevisiae, C. krusei, and C. lusitaniae were most effective against E. coli-OXA48. Unsupervised metabolite profiling data analysis with multiblock approach highlighted a clustering of samples according to yeast species. Regarding inhibitory power on E. coli (ATCC or OXA48), active supernatants tend to cluster together suggesting the presence of similar metabolites; some were further characterized. This study highlights the diverse interactions between E. coli and commensal yeasts. From an applied perspective, these findings pave the way for identifying probiotics or postbiotics with potential applications in combating multidrug-resistant bacteria through novel antimicrobial compounds.

microbiology↗

bioRxiv2023

Discovery of New Broad-Spectrum Anti-Infectives for Eukaryotic Pathogens Using Bioorganometallic Chemistry

Drug resistance observed with many anti-infectives clearly highlights the need for new broad-spectrum agents to treat especially neglected tropical diseases (NTDs) caused by eukaryotic parasitic pathogens including fungal infections. Since these diseases target the most vulnerable communities who are disadvantaged by health and socio-economic factors, new agents should be, if possible, easy-to-prepare to allow for commercialization based on their low cost. In this study, we show that simple modification of one of the most well-known antifungal drugs, fluconazole, with organometallic moieties not only improves the activity of the parent drug but also broadens the scope of application of the new derivatives. These compounds were highly effective in vivo against pathogenic fungal infections and potent against parasitic worms such as Brugia, which causes lymphatic filariasis and Trichuris, one of the soil-transmitted helminths that infects millions of people globally. Notably, the identified molecular targets indicate a mechanism of action that differs greatly from the parental antifungal drug, including targets involved in biosynthetic pathways that are absent in humans, offering great potential to expand our armamentarium against drug-resistant fungal infections and NTDs targeted for elimination by 2030. Overall, the discovery of these new compounds with broad-spectrum activity opens new avenues for the development of treatments for several current human infections, either caused by fungi or by parasites, including other NTDs, as well as newly emerging diseases. ONE-SENTENCE SUMMARYSimple derivatives of the well-known antifungal drug fluconazole were found to be highly effective in vivo against fungal infections, and also potent against the parasitic nematode Brugia, which causes lymphatic filariasis and against Trichuris, one of the soil-transmitted helminths that infects millions of people globally.

pharmacology and toxicology↗