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 from having 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 NF-κB 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.

The role of the PI3K/AKT signalling pathway in the corneal epithelium: recent updates

“…Most of the current drugs used to treat HSV are nucleoside analogues, which have a high incidence of side effects and target DNA replication. Fortunately, recent studies have identified several promising and safer drugs that target the AKT signalling pathway to inhibit HSV infection in the cornea, including the natural secondary metabolite prodigiosin (PD), which is produced by Serratia marcescens , and a selective 3-phosphoinositide-dependent kinase 1 inhibitor called BX795 [ 108 , 109 ]. And the inhibitory effect of PD on HSV-1 in vivo, in vitro, and ex vivo, with positive therapeutic results observed in mouse models.…”

“…And the inhibitory effect of PD on HSV-1 in vivo, in vitro, and ex vivo, with positive therapeutic results observed in mouse models. PD treatment may inhibit the phosphorylation of AKT in CECs, preventing it from inactivating GSK3β, blocking apoptosis, promoting protein synthesis, and creating a host environment that facilitates viral replication [ 109 ]. Moreover, BX795 inhibits the PI3K/AKT/mTOR pathway and then blocks the hyperphosphorylation of eukaryotic initiation factor 4E-binding protein 1, which is a member of a family of translation repressor proteins [ 110 , 111 ].…”

Prodigiosin: a promising biomolecule with many potential biomedical applications

“…Another interesting study recently performed by Suryawanshi et al . evaluated the antiviral activity of PG against Herpes simplex virus (HSV) 1 and 2 [ 121 ]. It was observed that 2.5 µM PG strongly inhibited HSV-1 infection in human corneal epithelial (HCE) cells, a physiologically relevant in vitro model.…”

Brought to you courtesy of the red, white, and blue–pigments of nontuberculous mycobacteria

“…Prodigiosin also demonstrates activity against chloroquine-resistant strain Plasmodium falciparum , induces synthesis of autolysins in Bacillus cereus, and stimulates production of ROS that prevents formation of biofilm in P. aeruginosa [56] , [59] . In the case of herpes simplex virus type 1 and 2, prodigiosin exerts antiviral activity by inhibiting NF-κB and Akt signaling pathways in vitro and ex vivo in cultured porcine corneas [60] . The pathway in which prodigiosin provides antiviral relief involves the inhibition of anti-apoptotic activity of TNF-α mediated by NF-κB [60] .…”

“…In the case of herpes simplex virus type 1 and 2, prodigiosin exerts antiviral activity by inhibiting NF-κB and Akt signaling pathways in vitro and ex vivo in cultured porcine corneas [60] . The pathway in which prodigiosin provides antiviral relief involves the inhibition of anti-apoptotic activity of TNF-α mediated by NF-κB [60] . Applications: Prodigiosin has been used in food coloration to replace the synthetic pigments used in the food industry, coloration of polyolefines, as well as applied in sunscreen to increase the sunscreen protection factor [61] .…”