title: The effect of bulgecin A on peptidoglycan metabolism and physiology of Helicobacter pylori.
abstract: Helicobacter pylori, a human-specific bacterial pathogen responsible for severe gastric diseases, constitutes a major public health issue. In the last decade, rates of H. pylori resistance to antibiotics were increasing drastically, requiring alternative therapeutic strategies to deal with eradication failures. Therefore, we evaluated the potential of bulgecin A, a glycosidic inhibitor of the lytic transglycosylase (LTG) Slt70 of Escherichia coli, as a new therapeutic approach against the H. pylori infection. In this study, we show that bulgecin A is able to specifically inactivate the H. pylori LTG Slt, but not its ortholog MltD. Moreover, bulgecin A synergized with amoxicillin, an inhibitor of penicillin binding proteins, inducing strong morphological alterations, cellular damages, and cell death. Similarly, the simultaneous inactivation of the peptidoglycan (PG) peptidase HdpA and Slt led to inhibition of H. pylori growth, highlighting the strong potential of targeting the PG biosynthetic pathway at different biochemical steps to enhance our therapeutic approaches against bacteria. Hence, we propose that bulgecin A constitutes an attractive compound for the development of new therapeutic strategies against H. pylori combined with other inhibitors of PG biosynthetic enzymes.
authors.affiliation: Institut Pasteur , Group Biology and Genetics of the Bacterial Cell Wall, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Bonis
authors.forename: Allison
authors.initials: A
authors.lastname: Williams
authors.forename: Stephanie
authors.initials: S
authors.lastname: Guadagnini
authors.forename: Catherine
authors.initials: C
authors.lastname: Werts
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Boneca
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000658:Amoxicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002473:Cell Wall / Q000737:chemistry; D004357:Drug Synergism; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D016481:Helicobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors; D010457:Peptidoglycan / Q000096:biosynthesis; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; C051467:peptidoglycan endopeptidase; D000658:Amoxicillin; C405349:bulgecin A; D011392:Proline; D006026:Glycoside Hydrolases; C085428:slt protein, E coli; D010450:Endopeptidases; D000117:Acetylglucosamine