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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)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 2451-9448
e-ISSN 2451-9456
Journal Cell Chemical Biology
Quellenangaben Volume: 30, Issue: 5, Pages: 499-512.e5 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Massachusetts
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-502700-001
Grants 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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