Peptidoglycan-Associated Cyclic Lipopeptide Disrupts Viral Infectivity

Abstract

Enteric viruses exploit bacterial components, including lipopolysaccharides (LPS) and peptidoglycan (PG), to facilitate infection in humans. Because of their origin in the bat enteric system, we wondered if severe acute respiratory syndrome coronavirus (SARS-CoV) or Middle East respiratory syndrome CoV (MERS-CoV) also use bacterial components to modulate infectivity. To test this question, we incubated CoVs with LPS and PG and evaluated infectivity, finding no change following LPS treatment. However, PG from Bacillus subtilis reduced infection Ͼ10,000-fold, while PG from other bacterial species failed to recapitulate this. Treatment with an alcohol solvent transferred inhibitory activity to the wash, and mass spectrometry revealed surfactin, a cyclic lipopeptide antibiotic, as the inhibitory compound. This antibiotic had robust dose-and temperature-dependent inhibition of CoV infectivity. Mechanistic studies indicated that surfactin disrupts CoV virion integrity, and surfactin treatment of the virus inoculum ablated infection in vivo. Finally, similar cyclic lipopeptides had no effect on CoV infectivity, and the inhibitory effect of surfactin extended broadly to enveloped viruses, including influenza, Ebola, Zika, Nipah, chikungunya, Una, Mayaro, Dugbe, and Crimean-Congo hemorrhagic fever viruses. Overall, our results indicate that peptidoglycan-associated surfactin has broad viricidal activity and suggest that bacteria by-products may negatively modulate virus infection. IMPORTANCE In this article, we consider a role for bacteria in shaping coronavirus infection. Taking cues from studies of enteric viruses, we initially investigated how bacterial surface components might improve CoV infection. Instead, we found that peptidoglycan-associated surfactin is a potent viricidal compound that disrupts virion integrity with broad activity against enveloped viruses. Our results indicate that interactions with commensal bacterial may improve or disrupt viral infections, highlighting the importance of understanding these microbial interactions and their implications for viral pathogenesis and treatment.

Gut Microbiota Status in COVID-19: An Unrecognized Player?

“…The molecule responsible for CoV inhibition is surfactin, a cyclic lipopeptide (CLP), that presents dose and temperature dependent virucidal properties. It is known that surfactin can reduce infection by other enveloped viruses, such as that of influenza A, Zika, Dugbe, Nipah, Crimean-Congo hemorrhagic fever, chikungunya, Mayaro, Una, and Ebola viruses (Johnson et al, 2019). This evidence confirms the role for commensal bacteria in increasing or decreasing viral infection, suggesting the importance of microbiota in viral pathogenesis and treatment.…”

“…The absence of LPS binding toll-like receptor (TLR) 4 resulted in augmented disease (Totura et al, 2015), due to the TLR pathways role in immunity to SARS-CoV. Johnson et al (2019) explored the relationship between bacterial surface components and CoV infection, and found that PG from Bacillus subtilis reduced CoV infectivity. The molecule responsible for CoV inhibition is surfactin, a cyclic lipopeptide (CLP), that presents dose and temperature dependent virucidal properties.…”

Virus interactions with bacteria: Partners in the infectious dance

“…Bacterial products can also impact viral infectivity. Surfactin, a cyclic lipopeptide with membrane disruptive properties produced by Bacillus subtilis [27], disrupts coronavirus virion integrity and impairs the infectivity of several enveloped viruses, including Chikungunya, Crimean-Congo hemorrhagic fever, Dugbe, Ebola, IAV, Mayaro, Nipah, Una, and Zika [28]. It is conceivable that as-yet-unidentified metabolites and natural products produced by the bacterial component of the microbiota impact viral infectivity.…”

Novel Ionophores Active against La Crosse Virus Identified through Rapid Antiviral Screening

“…Because we observed significant reductions in LACV titers with valinomycin treatment, we hypothesized that valinomycin might directly affect cellular processes to reduce virus infection. Nonetheless, valinomycin is a cyclic peptide and could potentially directly inactivate viral particles, as seen previously (23). To test whether valinomycin directly reduced virus infectivity, we directly incubated LACV with 2 M valinomycin for 24 h and directly determined the titer of the surviving virus at regular intervals.…”