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bioRxiv · 10.1101/2023.05.25.542268

Roles of Lipopolysaccharide Glycosyltransferases in Maintenance of Helicobacter pylori Morphology, Cell Wall Permeability, and Antimicobial Susceptibilities

Tang, X.·Yang, T.·Shen, Y.-L.·Song, X.·Benghezal, M.·Marshall, B.·Tang, H.·Li, H.
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Abstract

Helicobacter pylori unique lipopolysaccharide structure is essential in maintaining the cell envelop integrity and renders the bacterium natural resistance to cationic antimicrobial peptides (CAMPs). Our group has recently elucidated the complete set of LPS glycosyltransferase genes in H. pylori reference strain G27. Here, with a series of 8 systematically constructed LPS glycosyltransferase gene mutants (G27{Delta}HP1578, G27{Delta}HP1283, G27{Delta}HP0159, G27{Delta}HP0479, G27{Delta}HP0102, G27{Delta}wecA, G27{Delta}HP1284 and G27{Delta}HP1191), we investigated the roles of H. pylori LPS glycosyltransferases in maintenance of cell morphology, cell wall permeability, and antimicrobial susceptibilities. We demonstrated that deletion of these LPS glycosyltransferase genes did not interfere with bacterial cell wall permeability, but resulted in significant morphological changes (coccoid, coiled "c"-shape, and irregular shapes) after 48 h growth as compared to the rod-like cell shape of the wild-type strain. Moreover, as compared with the wild-type, none of the LPS mutants had altered susceptibility against clarithromycin, levofloxacin, amoxicillin, tetracycline, and metronidazole. However, the deletion of the conserved LPS glycosyltransferases, especially the O-antigen initiating enzyme WecA displayed a dramatic increase in susceptibility to the CAMP polymyxin B and rifampicin. Taken together, our findings suggest that the LPS glycosyltransferases play critical roles in the maintenance of the typical spiral morphology of H. pylori, as well as resistance to CAMPs and rifampicin. The LPS glycosyltransferases could be promising targets for developing novel anti-H. pylori drugs. ImportanceH. pylori typical helical morphology, cell wall integrity, as well as resistance to cationic CAMPs and antimicrobials are significant factors for its long-term colonization and persistent infection in human gastric mucosa. Our results show that each of the 8 LPS glycosyltransferase genes (HP1578, HP1283, HP0159, HP0479, HP0102, wecA, HP1284 and HP1191) deletion did not interfere with bacterial cell wall permeability, but resulted in significant loss of H. pylori typical helical shape. Furthermore, deletion of the conserved LPS glycosyltransferases, especially the O-antigen initiating enzyme WecA displayed a dramatic increase in susceptibility to the CAMP polymyxin B and rifampicin. Taken together, we believe that the LPS glycosyltransferases are good targets for developing novel anti-H. pylori drugs.

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Tang, X., Yang, T., Shen, Y.-L., Song, X., Benghezal, M., Marshall, B., Tang, H., Li, H.. 2023-05-25. Roles of Lipopolysaccharide Glycosyltransferases in Maintenance of Helicobacter pylori Morphology, Cell Wall Permeability, and Antimicobial Susceptibilities. https://doi.org/10.1101/2023.05.25.542268

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