Abstract
Antimicrobial resistance is a global health crisis and few novel antimicrobials have been discovered in recent decades. Natural products, particularly from Streptomyces, are the source of most antimicrobials, yet discovery campaigns focusing on Streptomyces from the soil largely rediscover known compounds. Investigation of understudied and symbiotic sources has seen some success, yet no studies have systematically explored microbiomes for antimicrobials. Here we assess the distinct evolutionary lineages of Streptomyces from insect microbiomes as a source of new antimicrobials through large-scale isolations, bioactivity assays, genomics, metabolomics, and in vivo infection models. Insect-associated Streptomyces inhibit antimicrobial-resistant pathogens more than soil Streptomyces. Genomics and metabolomics reveal their diverse biosynthetic capabilities. Further, we describe cyphomycin, a new molecule active against multidrug resistant fungal pathogens. The evolutionary trajectories of Streptomyces from the insect microbiome influence their biosynthetic potential and ability to inhibit resistant pathogens, supporting the promise of this source in augmenting future antimicrobial discovery.
Highlights
Antimicrobial resistance is a global health crisis and few novel antimicrobials have been discovered in recent decades
Natural products are the main source of antimicrobials, the majority of which are produced by Actinobacteria cultured from the soil[3,4]
These symbioses are best exemplified in fungus-growing ant[19,20,21], solitary digger wasp[22], and southern pine beetle[23] (Fig. 1a, right) systems, where Actinobacteria provide chemical defenses, paralleling our own reliance on the antimicrobials produced by these taxa to combat infectious disease
Summary
Antimicrobial resistance is a global health crisis and few novel antimicrobials have been discovered in recent decades. A compelling source of novel antimicrobials lies in defensive symbioses, where bacterial symbionts produce antimicrobials to protect against opportunistic and specialized pathogens[19,20,21,22,23] In insects, these symbioses are best exemplified in fungus-growing ant[19,20,21], solitary digger wasp[22], and southern pine beetle[23] (Fig. 1a, right) systems, where Actinobacteria (typically Streptomyces) provide chemical defenses, paralleling our own reliance on the antimicrobials produced by these taxa to combat infectious disease. Over 10 new natural products with antimicrobial activity have been identified from the chemical characterization of approximately
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