Killing two birds with one stone – Prenylated flavonoids disrupt the lethal synergism of influenza A viruses and pneumococci

Influenza is one of the most significant viral pathogens worldwide. Its enormous impact on public health is aggravated due to severe complications caused by bacteria such as Streptococcus pneumoniae [1]. Recently, a viral neuraminidase (NA) mediated lethal synergism between influenza viruses and pneumococci was described [2]. Since structurally similar NAs are present on the surface of both, viruses and bacteria, dual NA inhibitors are considered a promising strategy in drug discovery.

In this study, constituents of the traditional Chinese flu remedy sāng bái pí (Morus alba L. root bark) were investigated for their ability to disrupt the lethal synergism.

Distinct inhibition of viral and pneumococcal NAs was measured for two isolated prenylated flavonoid derivatives, sanggenon G and sanggenol A. Importantly, and in contrast to oseltamivir (Tamiflu^®), these compounds also inhibited bacterial biofilm formation.

Based on these findings, 27 congeners of sanggenol A (non-, mono-, and di-prenylated compounds) were evaluated, and a direct correlation between the degree of prenylation and bioactivity was observed. The most promising compound, the di-prenylated flavanone abyssinone-V 4'-methyl ether (27), inhibited pneumococcal NA with IC₅₀= 2.18µM, pneumococcal growth with MIC = 5.63µM, and biofilm formation with MBIC = 4.21µM, without harming lung epithelial cells [3]. Its anti-pneumococcal activity was visualized by scanning electron microscopy (see Figure below). Both, sanggenol A and compound 27 disrupted the lethal synergism of influenza viruses and pneumococci. They caused a significant reduction of the viral yield in A549 cells in the presence, as well as in the absence of pneumococcal NA (NanA) [3].

In this work, a clear rationale for the anti-infective potential of sāng bái pí was derived that can serve as a starting point for the discovery of effective drugs based on natural products.

Keywords: influenza virus, pneumonia, Streptococcus pneumoniae, prenylated flavonoids.

References:

[1] Buommino E, Scognamiglio M, Donnarumma G, Fiorentino A, D'Abrosca B. Recent advances in natural product-based anti-biofilm approaches to control infections. Mini-Rev Med Chem 2014; 14: 1169 – 1182

[2] McCullers JA. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat Rev Microbiol 2014; 12: 252 – 262

[3] Grienke U, Richter M, Walther E, Hoffmann A, Kirchmair J, Makarov V, Nietzsche S, Schmidtke M, Rollinger JM. Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae. Sci Rep 2016; 6: 27156. DOI: 10.1038/srep27156