Morin Moderates the Biotoxicity of Pneumococcal Pneumolysin by Weakening the Oligomers’ Formation

Abstract

Streptococcus pneumoniae (pneumococcus) is an important causative agent of acute invasive and non-invasive infections. Pneumolysin is one of a considerable number of virulence traits produced by pneumococcus that exhibits a variety of biological activities, thus making it a target of small molecule drug development. In this study, we aimed to evaluate the effect of morin, a natural compound that has no antimicrobial activity against S. pneumonia, is a potent neutralizer of pneumolysin-mediated cytotoxicity and genotoxicity by impairing oligomer formation, and possesses the capability of mitigating tissue damage caused by pneumococcus. These findings indicate that morin could be a potent candidate for a novel therapeutic or auxiliary substance to treat infections for which there are inadequate vaccines and that are resistant to traditional antibiotics.

Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia

“…The various PLY antagonists identified, none of which was found to possess antimicrobial activity, effectively attenuated the hemolytic activity of PLY, as well as the injurious effects of the toxin on an alveolar epithelial cell line in vitro [ 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. In addition, subcutaneous administration of these various natural antagonists of PLY resulted in significantly improved survival in a murine model of intranasal pneumococcal lung infection [ 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. The various members of each category of natural antagonists of PLY are summarized as follows: phytosterols : β-sitosterol was initially identified as a cholesterol-mimic, interacting with the conserved cholesterol-binding site located on domain 4 of PLY, with potency comparable with that of cholesterol [ 99 ].…”

“…Unlike the phytosterols, the polyphenol antagonists appear to interfere with the oligomerization of PLY monomers on the target cell membrane via binding to the cleft between domains 3 and 4 of the toxin molecule [ 101 , 102 ] bioflavonoids : three bioflavonoids viz. apigenin (4′,5,7-trihyddroxyflavone) [ 103 ], morin [2-(2,4-dihydroxyphenol)-3,5,7-trihydroxychromen-4-one] [ 104 ] and amentoflavone {8-[5-(5,7-dihydroxy-4-oxo-chromen-2-yl)-2-hydroxy-phenyl]-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one} [ 105 ] have also been found to attenuate the harmful activities of PLY. All three agents were found to cause inhibition of the hemolytic activity of PLY at concentrations of around 16 µg/mL by apparent interference with the oligomerization of toxin monomers [ 103 , 104 , 105 ] naphthoquinones: two members of this class of chemical agent viz.…”

“…apigenin (4′,5,7-trihyddroxyflavone) [ 103 ], morin [2-(2,4-dihydroxyphenol)-3,5,7-trihydroxychromen-4-one] [ 104 ] and amentoflavone {8-[5-(5,7-dihydroxy-4-oxo-chromen-2-yl)-2-hydroxy-phenyl]-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one} [ 105 ] have also been found to attenuate the harmful activities of PLY. All three agents were found to cause inhibition of the hemolytic activity of PLY at concentrations of around 16 µg/mL by apparent interference with the oligomerization of toxin monomers [ 103 , 104 , 105 ] naphthoquinones: two members of this class of chemical agent viz. shikonin {also known as alkanin: 5,8-dihydroxy-2-[(1 S )-1-hydroxy-4-methylpent-3-en-1 yl]naphthalene-1,4-dione} [ 106 ] and juglone (5-hydroxy-1,4-naphthalenedione) [ 107 ] have also been reported to inhibit the pore-forming activity of PLY via interference with toxin oligomerization.…”

“…apigenin (4′,5,7-trihyddroxyflavone) [ 103 ], morin [2-(2,4-dihydroxyphenol)-3,5,7-trihydroxychromen-4-one] [ 104 ] and amentoflavone {8-[5-(5,7-dihydroxy-4-oxo-chromen-2-yl)-2-hydroxy-phenyl]-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one} [ 105 ] have also been found to attenuate the harmful activities of PLY. All three agents were found to cause inhibition of the hemolytic activity of PLY at concentrations of around 16 µg/mL by apparent interference with the oligomerization of toxin monomers [ 103 , 104 , 105 ]…”

Matcha Green Tea Exhibits Bactericidal Activity against Streptococcus pneumoniae and Inhibits Functional Pneumolysin

“…Commonly prescribed cholesterol-lowering statins have been shown to reduce lung tissue damage by inhibiting PLY activity [ 16 ]. In addition, some natural compounds that inhibit PLY oligomerization have been reported to attenuate pneumococcal infection [ 17 , 18 , 19 ].…”