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bioRxiv · 10.1101/500645

Impact of branching on the conformational heterogeneity of the lipopolysaccharide from Klebsiella pneumoniae: Implications for vaccine design

Aytenfisu, A.·Simon, R.·MacKerell, A.
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Abstract

Resistance of Klebsiella pneumoniae (KP) to antibiotics has motivated the development of an efficacious KP human vaccine that would not be subject to antibiotic resistance. Klebsiella lipopolysaccharide (LPS) associated O polysaccharide (OPS) types have provoked broad interest as a vaccine antigen as there are only 4 that predominate worldwide (O1, O2a, O3, O5). Klebsiella O1 and O2 OPS are polygalactans that share a common D-Gal-I structure, for which a variant D-Gal-III was recently discovered. To understand the potential impact of this variability on antigenicity, a detailed molecular picture of the conformational differences associated with the addition of the D-Gal-III (1[->]4)Gal branch is presented using enhanced-sampling molecular dynamics simulations. In D-Gal-I two major conformational states are observed while the presence of the 1[->]4 branch in D-Gal-III resulted in only a single dominant extended state. Stabilization of the more folded states in D-Gal-I is due to a O4-H...O2 hydrogen bond in the linear backbone that cannot occur in D-Gal-III as the O4 is in the Galp(1[->]4)Galp glycosidic linkage. The impact of branching in D-Gal-III also significantly decreases the accessibility of the monosaccharides in the linear backbone region of D-Gal-I, while the accessibility of the terminal D-Gal-II region of the OPS is not substantially altered. The present results suggest that a vaccine that targets both the D-Gal-I and D-Gal-III LPS can be developed by using D-Gal-III as the antigen combined with cross-reactivity experiments using the Gal-II polysaccharide to assure that this region of the LPS is the primary epitope of the antigen.\n\nAuthor SummaryKlebsiella pneumoniae (KP) is a bacterial pathogen commonly associated with hospital acquired infections to antibiotics and is of increasing concern due to the development of resistance to antibiotics including those of last resort. Development of an efficacious KP human vaccine would not be subject to the mechanisms governing antibiotic resistance and, is thus, a public health priority. The present study applies computer simulations to understand the effects of branching on the antigenic D-Gal-I and D-Gal-III O polysaccharide (OPS) species of KP. Results show that branching leads to a single dominate extended conformation, though that conformation occurs in both species. In addition, the terminal D-Gal-II region of both OPS sample similar, exposed conformations while regions of the central repeating units of the OPS are potential hindered from interactions with antibodies in the presence of the branched D-Gal-III OPS. The results suggest a strategy for vaccine development based on D-Gal-III as the antigen combined with cross reactivity experiments to assure that the D-Gal-II region is the primary epitope of the antigen.

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Aytenfisu, A., Simon, R., MacKerell, A.. 2018-12-18. Impact of branching on the conformational heterogeneity of the lipopolysaccharide from Klebsiella pneumoniae: Implications for vaccine design. https://doi.org/10.1101/500645

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