NEW YORK (GenomeWeb) – A team led by investigators at the University of Wisconsin at Madison has identified a potential antifungal compound through a natural product search that centered on Streptomyces bacteria in insect microbiomes.
The researchers used metagenomics, targeted sequencing, whole-genome sequencing, metabolomics, bioactivity assays, and other approaches to compare Streptomyces representatives in microbial communities in soil samples or insect samples. Their results, published online yesterday in Nature Communications, suggest that the forms of Streptomyces found in insect-associated microbiomes produce more robust antimicrobial compounds that those in soil microbiomes.
In particular, the team's analyses highlighted a natural product called cyphomycin from the microbiome of a fungus-growing ant that showed pronounced antifungal activity — including activity against multidrug-resistant fungal pathogens such as Aspergillus fumigatus — in follow-up experiments.
"Our validation of Streptomyces from insect microbiomes as a rich source of bioactive natural products demonstrates the extensive opportunities for antimicrobial discovery within the vast chemical diversity of these microbial communities," corresponding author Cameron Currie, a bacteriology researcher at the University of Wisconsin-Madison, and his colleagues wrote.
The team focused on Streptomyces bacteria, reasoning that the genus has already yielded natural products with antibacterial and antifungal activity. In an effort to expand the repertoire of antimicrobial compound-producing Streptomyces representatives, though, the authors looked to the insect microbiome, arguing that "discovery campaigns focusing on Streptomyces from the soil largely rediscover known compounds."
Although primarily thought of as soil microbes, we show Streptomyces from phylogenetically distinct lineages commonly form associations with diverse insect hosts," they wrote.
To that end, the researchers used shotgun metagenomics on samples from more than 2,500 insects to isolate nearly 10,200 Streptomyces isolates from 1,445 species from 13 insect orders. They found thousands more Streptomyces isolates in 833 soil and 980 plant samples, making it possible to place the insect-associated forms of Streptomyces in a phylogenetic context.
After bioactivity assays revealed promising antimicrobial activity in insect-associated isolates, the investigators turned to whole-genome sequencing, 16S ribosomal RNA gene sequencing, and liquid chromatography-mass spectrometry-based metabolomics to explore the relationship between Streptomyces phylogeny, bioactivity, and metabolomic profiles for 120 strains — analyses that revealed distinct, insect-associated lineages within the Streptomyces genera that produced phylogeny-related chemical fingerprints.
"The evolutionary trajectories of Streptomyces from the insect microbiome influence their biosynthetic potential and ability to inhibit resistant pathogens," the authors wrote, "supporting the promise of this source in augmenting future antimicrobial discovery."
Indeed, the team's subsequent in vitro and in vivo experiments in mouse models of pathogen infections led to the antifungal compound cyphomycin, produced by a Brazilian Streptomyces strain isolated from Cyphomyrmex ants, which appeared to inhibit several fungi that act as pathogens in human or ant hosts.
"Together, activity against multidrug-resistant fungi in vitro coupled with high efficacy in in vivo mouse models of infection highlight cyphomycin's potential as a drug lead to treat multidrug resistant fungal infections," they concluded.