NMR-based metabolomics—whether applied independently or harmonized with genomics—offers a potent lens into microbes' chemical repertoire. The judicious integration of artificial intelligence (AI) further amplifies the potential of this advanced methodology, ushering in new frontiers for microbial natural products discovery.

Archangiumide is a unique macrolide natural product that features an endocyclic allene functionality, rendering it a prototype of a new class of secondary metabolites of microbial origin. However, its biological and/or pharmaceutical roles remain obscure. In this study, we have unveiled an antiviral potency of archangiumide that was effective against herpes simplex virus (HSV-1) replication. We found that archangiumide did not affect host cell viability, nor pathogen infectivity, but suppressed HSV-1 early replication, in terms of early replication genes, such as ICP0, ICP4, etc. Further scrutinizing the underlined master regulator, we found that HSV-1 VP16 protein expression was inhibited by archangiumide, as well as VP16 nuclear translocation. As VP16 is a coactivator of transcription, archangiumide harnessed the master regulator of HSV-1 early replication. Together, here we provide evidence that allene macrolide archangiumide possesses robust antiviral functions that may be valuable for a novel viral infection intervention, as macrolides are generally safe drugs for prolonged treatments.