Bacterial Pigment Prodigiosin Demonstrates a Unique Antiherpesvirus Activity That Is Mediated through Inhibition of Prosurvival Signal Transducers

Abstract

Herpes simplex virus (HSV) is among the most prevalent viral infections worldwide and remains incurable. While nucleoside analogs are used to relieve symptoms of infection, they suffer serious adverse effects and are unable to abolish the virus from the host. Here, we demonstrate a unique antiviral effect of prodigiosin (PG), a natural secondary metabolite produced by Serratia marcescens, on HSV infection. We show that PG naturally exerts antiviral activity against HSV-1 and HSV-2 infections.PG treatment resulted in robust inhibition of viral replication in-vitro and ex-vivo in cultured porcine corneas. Additionally, PG protected against HSV-1 infection and disease progression in a murine model of ocular infection. In our quest to determine the molecular mechanisms of its antiviral activity, we show that PG specifically inhibits NFκB and Akt signaling pathways and promotes accelerated cell death in HSV infected cells. Our findings reveal novel antiviral properties of PG, suggesting its high potential as an alternative treatment for herpetic diseases. They also provide new information on antiviral effects of HSV-bacterial metabolite interactions. IMPORTANCE In this article, we provide a new role for a commonly found bacterial pigment in controlling herpes simplex virus infection for which diverse and multimodal antiviral agents are needed to prevent drug resistance. Serratia marcescens is a red pigment (prodigiosin) producing gram-negative bacillus that is naturally found in soil and water. It is associated with many kinds of human infections including wound and eye infections, and meningitis. Taking cues from previous studies on prodigiosin including possible proapoptotic anticancer properties, we investigated how it might affect HSV infection. Interestingly, we found that it is a potent virucidal compound that disrupts host signaling pathways needed for HSV growth and survival. The mode of antiviral action suggests potentially broad activity against enveloped viruses. Our results also indicate that interactions with commensal bacteria may inhibit HSV infection, underscoring the importance of studying these microbial metabolites and their implications for viral pathogenesis and treatment.