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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Selective killing of the human gastric pathogen Helicobacter pylori by mitochondrial respiratory complex I inhibitors.
Cell Chem. Bio. 30, 499-512.e5 (2023)
Respiratory complex I is a multicomponent enzyme conserved between eukaryotic cells and many bacteria, which couples oxidation of electron donors and quinone reduction with proton pumping. Here, we report that protein transport via the Cag type IV secretion system, a major virulence factor of the Gram-negative bacterial pathogen Helicobacter pylori, is efficiently impeded by respiratory inhibition. Mitochondrial complex I inhibitors, including well-established insecticidal compounds, selectively kill H. pylori, while other Gram-negative or Gram-positive bacteria, such as the close relative Campylobacter jejuni or representative gut microbiota species, are not affected. Using a combination of different phenotypic assays, selection of resistance-inducing mutations, and molecular modeling approaches, we demonstrate that the unique composition of the H. pylori complex I quinone-binding pocket is the basis for this hypersensitivity. Comprehensive targeted mutagenesis and compound optimization studies highlight the potential to develop complex I inhibitors as narrow-spectrum antimicrobial agents against this pathogen.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Cag Type Iv Secretion System ; Helicobacter Pylori ; Antibiotic Resistance ; Narrow-spectrum Antibiotics ; Pathogen Blockers ; Pathogenicity Factors ; Quinone-binding Cavity ; Respiratory Complex I ; Small-molecule Inhibitors; Nadh-ubiquinone Oxidoreductase; Antibiotic-resistance; Campylobacter-jejuni; Escherichia-coli; Gene-transfer; Secretion; Evolution; Cancer; Caga; Strategies
ISSN (print) / ISBN
2451-9448
e-ISSN
2451-9456
Zeitschrift
Cell Chemical Biology
Quellenangaben
Band: 30,
Heft: 5,
Seiten: 499-512.e5
Verlag
Cell Press
Verlagsort
Cambridge, Massachusetts
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Virology (VIRO)
Förderungen
German Center for Infection Research (DZIF)