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Lettl, C.* ; Schindele, F.* ; Mehdipour, A.R.* ; Steiner, T.* ; Ring, D.* ; Brack-Werner, R. ; Stecher, B.* ; Eisenreich, W.* ; Bilitewski, U.* ; Hummer, G.* ; Witschel, M.* ; Fischer, W.* ; Haas, R.*

Selective killing of the human gastric pathogen Helicobacter pylori by mitochondrial respiratory complex I inhibitors.

Cell Chem. Bio. 30, 499-512.e5 (2023)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 2451-9448
e-ISSN 2451-9456
Zeitschrift Cell Chemical Biology
Quellenangaben Band: 30, Heft: 5, Seiten: 499-512.e5 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Massachusetts
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-502700-001
Förderungen German Center for Infection Research (DZIF)
DOI 10.1016/j.chembiol.2023.04.003
WOS ID 001003161300001
Scopus ID 85159158399
PubMed ID 37100053
Erfassungsdatum 2023-10-06
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